Study on the progression types of cancer in patients with breast cancer undergoing eribulin chemotherapy and tumor microenvironment

Abstract

Background: Recently, the concepts of progression due to pre-existing lesions (PPL) and progression due to new metastasis (PNM) have been proposed to differentiate the progression types of treatment-resistant cancers. Previously, the differences between these two progression types did not affect the determination of treatment strategies since both PPL and PNM are classified as progressive disease based on the response evaluation criteria in solid tumors (RECIST) diagnostic criteria. On the other hand, tumor infiltrating lymphocytes (TILs) are effective when used as indicators for monitoring the immune tumor microenvironment (iTME) in the cancer host, and TILs play an important role as biomarkers in predicting prognosis and therapeutic effects. This study focused on the progression types of cancer in patients undergoing eribulin chemotherapy. In addition, the iTME in individuals with PPL and PNM was evaluated using TILs as a marker.

Methods: Of the 52 patients with locally advanced or metastatic breast cancer who underwent chemotherapy with eribulin, 40 remained in the study, and 12 patients were dropout cases. The antitumor effect was evaluated based on the RECIST criteria using version 1.1. TILs were defined as the infiltrating lymphocytes within tumor stroma and were expressed in proportion to the field investigated. In PPL cases, the high-TIL group was considered as type I and the low-TIL group was classified as type II. In PNM cases, the high-TIL group was considered as type III and the low-TIL group was classified as type IV.

Results: In 19 cases, individuals with type I progression had significantly longer progression free survival and overall survival (OS) compared to those with type III progression (p = 0.040, p < 0.001, log-rank). Individuals with type I progression had significantly prolonged survival post progression compared to those with type II progression (p = 0.048, log-rank). A multivariate analysis that validate the effect of OS showed that these were independent factors of good prognosis (p = 0.003; hazard ratio [HR] = 0.065) (p = 0.006; HR = 0.105).

Conclusions: The effects of eribulin chemotherapy suggested that patients with progressive-type breast cancer that proliferates in a good iTME may have a good prognosis.

Keywords: Breast cancer; Eribulin; Progressive disease; Tumor microenvironment; Tumor-infiltrating lymphocytes.

Fig. 1

Consort diagram. A total of 322 patients with MBC underwent cancer treatment at Osaka City University Hospital from August 2000 to June 2013. In the present study, only 40 patients were included, and 270 patients with other drug therapies and 12 patients with dropout cases due to surgery or adverse events were excluded

Fig. 2

Differences in progression types and prognostic analysis. The 33 PPL group had a significantly longer PFS (p = 0.044, log-rank) (a) and OS (p = 0.017, log-rank) (b) compared to the 7 PNM group

Fig. 3

Effects of TIL expression and differences in progression type upon prognosis. In 19 cases, individuals with type I progression had significantly longer PFS compared to those with type III progression (p = 0.040, log-rank) (a). Furthermore, individuals with type I progression had significantly longer OS compared to those with type III and type II progression (p < 0.001 and p = 0.047, respectively; log-rank) (b)

Fig. 4

Survival post progression. Individuals with type I progression had significantly prolonged survival post progression (SPP) compared to those with type II progression (p = 0.048, log-rank)

Fig. 5

Forest plots. A univariate analysis that validate the effect of overall survival showed that “high objective response rate” and “progression due to pre-existing lesions and high-TILs” were considered as factors for a good prognosis (p = 0.006; HR = 0.160) (p = 0.020; HR = 0.221)