Research Article: Use of Tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer

Date Published: February 6, 2017

Publisher: Public Library of Science

Author(s): Shinichiro Kashiwagi, Yuka Asano, Wataru Goto, Koji Takada, Katsuyuki Takahashi, Satoru Noda, Tsutomu Takashima, Naoyoshi Onoda, Shuhei Tomita, Masahiko Ohsawa, Kosei Hirakawa, Masaichi Ohira, Aamir Ahmad.


Eribulin mesylate (eribulin) is currently indicated for treatment of locally advanced or metastatic breast cancer (MBC). It is a cytotoxic agent with unique mechanisms that suppress epithelial-mesenchymal transition (EMT) of cancer cells. On the other hand, Tumor-infiltrating lymphocytes (TILs), which are considered indicators of immune response monitoring, have been reported as prognostic factors and predictors of therapeutic efficacy. We thought that eribulin, which has an EMT-inhibiting mechanism, may produce an antitumor effect by improving the immune microenvironment, and in this study investigated the effects of breast cancer eribulin chemotherapy on the immune microenvironment with TILs as a marker.

TILs was evaluated in 52 patients with MBC who underwent chemotherapy with eribulin. The correlation between TILs evaluated according to the standard method, and prognosis, including the efficacy of eribulin chemotherapy, was investigated retrospectively.

Of the 52 MBC patients, 29 (55.8%) were in the high TILs group and 23 (44.2%) were in the low TILs group. The high TILs group included significantly more triple-negative breast cancer (TNBC) (p = 0.008) than the low TILs group. In an analysis of outcomes, TNBC patients in the high TILs group had significantly longer disease-free survival than TNBC patients in the low TILs group (p = 0.033, log-rank), but no significant differences were seen in all breast cancer patients (p = 0.489, log-rank) or in non-TNBC patients (p = 0.878, log-rank). In a multivariate analysis of recurrence in TNBC patients, being in the high TILs group was again an independent factor for a good outcome (p = 0.031, HR = 0.063).

The results of this study suggest that TILs may be useful as a predictive marker of the therapeutic effect of eribulin chemotherapy in TNBC.

Partial Text

Eribulin mesylate (eribulin) stops cell division by inhibiting microtubule extension [1–3], and has a mechanism of action that differs from other antimitotic drugs such as taxane and vinca alkaloids [2, 4, 5]. Thus, eribulin binds to microtubule ends and suppresses microtubule polymerization. Taxane binds extensively inside microtubules and suppresses shortening of microtubules by depolymerization. Vinca alkaloids bind to the external surface of microtubules and suppress both microtubule polymerization and depolymerization. Consequently, the anti-cancer effect differs among these agents. For example, in a phase III trial of eribulin (EMBRACE, Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus E7389), a significant prolongation of overall survival was observed in patients with locally advanced or metastatic breast cancer (MBC) after eribulin treatment even without an improvement in disease free survival [6]. This effect was partially explained by a decrease in the occurrence of new metastatic lesions with eribulin therapy, an effect that has not been demonstrated with other drugs. However, the precise mechanism of this clinically significant benefit has not yet been elucidated. Some of the unique anticancer effects of eribulin have emerged from experimental studies using cancer cells and tumor tissues [7, 8]. These include suppression of the epithelial-mesenchymal transition (EMT) of cancer cells and promotion of vascular remodeling in tumors.

EMT is observed when cancer spreads, and promotes cancer infiltration and metastasis by facilitating the ability of cancer cells to move and the breakdown of the extracellular matrix [22]. Cancer cells with induced EMT are known to acquire treatment resistance and to have enhanced properties as cancer stem cells [23]. It is also reported that inhibiting EMT improves the cancer immune microenvironment and enhances the antitumor immune response [24]. An enhanced antitumor immune response contributes not only to immunotherapy but also to the antitumor effect of conventional chemotherapy [11]. Thus, inhibition of EMT with eribulin chemotherapy is thought to enhance the antitumor immune response via improvement in the cancer immune microenvironment.

The results of this study suggest that TILs may be useful as a predictive marker of the therapeutic effect of eribulin chemotherapy in TNBC.