A gene signature to predict high tumor-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple-negative breast cancer.

Background: In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after neoadjuvant chemotherapy (NACT) is associated with better prognosis. Our objective was to develop a gene signature from pretreatment samples to predict the extent of TILs after NACT and then to test its prognostic value on survival. Patients and methods: Using 99 pretreatment samples, we generated a four-gene signature associated with high post-NACT TILs. Prognostic value of the signature on distant relapse-free survival (DRFS) was first assessed on the training set (n = 99) and then on an independent validation set (n = 115). Results: A four-gene signature combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 was developed in baseline samples to predict the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, this signature was associated with DRFS [hazard ratio (HR): 0.28, for a one-unit increase in the value of the four-gene signature, 95% confidence interval (CI): 0.13-0.63)]. In a multivariate analysis performed on an independent validation set, the four-gene signature was significantly associated with DRFS (HR: 0.17, 95% CI: 0.06-0.43). The four-gene signature added significant prognostic information when compared with the clinicopathologic pretreatment model (likelihood ratio test in the training set P = 0.004 and in the validation set P = 0.002). Conclusions: A four-gene signature predicts high levels of TILs after anthracycline-containing NACT and outcome in patients with TNBC and adds prognostic information to a clinicopathological model at diagnosis.

Breast cancer response to paclitaxel in vivo.

Clinical trials using neoadjuvant (primary, preoperative) chemotherapy demonstrate that breast cancer reduction relates to survival. To date, no pre-treatment pathologic, phenotypic, or genotypic tumor characteristics predict a patient's likely benefit from paclitaxel. This has led to pilot clinical studies that have attempted to identify whether early cellular responses in vivo can be used to predict the effectiveness of chemotherapy. A potential benefit of such predictive studies will be the ability to tailor specific therapeutic approaches to individual patients. Important issues surrounding this field include how to accurately measure and/or categorize the extent of tumor reduction, and how and when to assess breast cancer cellular responses in vivo. Preliminary data indicate that initial apoptotic responses are critical to tumor reduction, and that the timing of tumor samples for assessment of response is important. Although inherent complete resistance of breast cancer to paclitaxel occurs in a minority of patients, mechanisms of acquired or partial resistance require further study. However, the initial apoptotic response to paclitaxel has been shown to transiently reduce both cell density and intratumoral pressure, providing a window of time when there can be improved penetration of paclitaxel into the tumor. Thus a strong initial apoptotic response can set up a compounding benefit from subsequent treatments. Knowledge of breast cancer response to paclitaxel in vivo could lead to therapeutic strategies that enhance the apoptotic response and optimize the dosing schedule, to improve the tumor reduction for most patients.