MOLECULAR SIGNATURE OF TRIPLE NEGATIVE BREAST CANCER

In a study reported in the Journal of the National Cancer Institute, Liu et al performed global proteomic profiling in samples from patients with triple-negative breast cancer in an attempt to identify a risk signature. They identified a novel 11-protein signature that independently predicts distant metastasis and breast cancer mortality and that may help to avoid unnecessary adjuvant systemic therapy in this setting.

Study Details

In the study, frozen primary tumors were collected from 126 patients with lymph node–negative and triple-negative breast cancer who had not received adjuvant therapy. Global proteome profiling was conducted in an in-house training set (n = 63) and a multicenter test set (n = 63). Patients free of distant metastasis for ≥ 5 years after surgery were defined as good-prognosis patients.

Among the training set patients, mean age was 51 years (21% ≤ 40 years), 46% were postmenopausal, mean tumor size was 2.9 cm, 70% had grade 3 disease, and 40% had metastasis within 5 years, with a median follow-up of 117 months in good-prognosis patients. Among the multicenter test set patients, mean age was 56 years (14% ≤ 40 years), 59% were postmenopausal, mean tumor size was 2.6 cm, 68% had grade 3 disease, and 30% had metastasis within 5 years, with a median follow-up of 108 months in good-prognosis patients.

Training Set

In the training set, 11 proteins were identified as having significant association with prognosis. Of these, 10 were upregulated (CMPK1, AIFM1, FTH1, EML4, GANAB, CTNNA1, AP1G1, STX12, AP1M1, and CAPZB) and one was downregulated (MTHFD1) in good-prognosis patients. The area under the receiver operating curve for the 11-protein signature was 0.95.

Predicts Distant Metastasis, Breast Cancer Mortality

In the multicenter test set, 31 of 33 patients in the good-prognosis group did not develop distant metastasis, for a negative predictive value of 93.9%, whereas 17 of 30 poor-prognosis patients developed distant metastasis, for a positive predictive value of 56.7%. Overall, the 11-protein signature had sensitivity of 89.5% and specificity of 70.5% in predicting poor prognosis.

In multivariate analysis adjusting for traditional prognostic factors, the 11-protein signature was an independent predictor of poor outcome, with poor-prognosis patients having a hazard ratio (HR) of 12.45 (P = .001) for distant metastasis vs good-prognosis patients. Age, menopausal status, tumor size, and tumor grade were not independent predictors of distant metastasis. The 11-protein signature was also the sole independent predictor of breast cancer-related mortality on multivariate analysis, with poor-prognosis patients having a hazard ratio of 36.08 (P = .001) for cancer-related death vs good-prognosis patients.

Adjuvant Therapy Guidance?

The investigators stated that 91% (40 of 44) and 95% (38 of 40) of the good-prognosis patients would be classified as high-risk patients using St. Gallen and National Institutes of Health (NIH) clinical consensus criteria, respectively, with these patients thus potentially receiving apparently unnecessary adjuvant chemotherapy. By comparison, only 30% (13 of 44) of the good-prognosis patients in the test set would be considered candidates for adjuvant therapy with use of the 11 protein signature. Thus, “more than 60% of patients in the test would have been exempted from unnecessary adjuvant chemotherapy using the 11-protein signature as guidance, compared with St. Gallen and NIH criteria.”

The investigators concluded, “We report the first validated proteomic signature to assess the natural course of clinical [triple-negative breast cancer].” They noted, “[W]e have developed an 11-protein signature to predict [triple-negative breast cancer] patients who develop a distant metastasis with high sensitivity, specificity, positive predictive value, and negative predictive value…. Therefore, our signature could aid in clinical practice to avoid unnecessary treatment with adjuvant chemotherapy of [lymph node-negative triple-negative breast cancer] patients. Future prospective clinical trials are needed to further consolidate the validity of the 11-protein signature.”

Arzu Umar, PhD, of Erasmus University Medical Center-Erasmus MC Cancer Institute, is the corresponding author for the Journal of the National Cancer Institute article.

The study was supported by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, a Center for Translational Molecular Medicine Breast CARE project, and a Dutch Cancer Society project.