Abstract P5-04-01: The TRANSERI project: Effect of eribulin (E) in patients with metastatic breast cancer (mBC) on circulating TGFβ and TNFα. Relationship with outcome
Authors: Garrone O , Tonissi F , Lingua D , Vandone AM , Vivenza D , Denaro N , Lo Nigro C , Merlano MC 
Published: February 2018

Abstract
Background: E is approved for the treatment of mBC patients (pts) after failure of at least 2 previous chemotherapy (CT) regimens containing antracyclines and taxanes. Its mechanism of action interferes with microtubule leading to cell cycle arrest in G2/M phase and cell apoptosis.
An in vitro study in triple negative BC cell lines shows that exposure to E reverses epithelial mesenchimal transition (EMT) phenotype toward an epithelial morphology and induces changes of gene profiling and protein expression. Accordingly in mice E reduces metastatization and can reverse EMT. TGFβ is an immunosuppressive cytokine and a growth factor for cancer-associated fibroblasts (CAFs). In addition it drives EMT. TNFα synergizes with TGFβ to promote EMT.
While CAFs pave the way for metastatization, EMT permits cancer cells trafficking through the blood flow following CAFs and finally developing metastases.
The purpose of the study is to investigate whether E interferes with TGFβ and TNFα levels and if the changes correlate with the outcome and the metastatic spread.
Methods: Pts with mBC, after failure of at least 2 previous CT lines were treated with E delivered at 1.23 mg/m2, d 1–8 every 21 d. Blood levels of TGFβ and TNFα were determined at baseline, before cycle 3, 5 and at disease progression. The changes observed were correlated with the outcome and the metastatic spread.
Results: The study is ongoing. Here we report preliminary data on 16 pts who completed 3 cycles of E. No change of TNFα level was observed during treatment. On the contrary, TGFβ levels changed during treatment.
Basal levels of TGFβ were divided in upper or lower the median (m) value. We did not observe any difference in m PFS between high or low values (137 d vs 141). However the m TGFβ value in pts was much higher than that observed in 3 healthy volunteers (m concentrations: 205 pg/ml [C.I. 115-920] vs 108 pg/ml [C.I. 85-120] respectively).
In 5 pts, TGFβ increased between cycle 1 and cycle 3, while diminished in 11 pts. We observed a numerical difference in PFS between the pts with decreased and increased values (150 d vs 85, p=NS).
We then divided the population in 3 groups: pts with TGFβ increased more than 25% of their basal levels (increased), pts with changes between +25% and -25% compared to their basal levels (stable) and pts with decreased values more than 25% of their basal levels (decreased). Comparing “increased” vs “stable” + “decreased” we observed a trend toward longer PFS favouring the latter group (77 d vs 144 p=0.12).
We collected the third determination in 14 pts. We did not analyse these data yet. However we observed that in 6 pts, TGFβ continues to decline. None of these pts progressed. In these pts the m value of TGFβ approaches healthy controls value (m concentrations: 180 pg/ml [C.I. 200-100] vs 108 pg/ml [C.I. 85-120]).
Conclusions: TNFα does not change during E treatment. On the contrary, TGFβ changes compared to basal levels. In pts with increased TGFβ between cycle 1 and 3 the PFS is lower than that observed in pts with stable or decreased levels (p=0.12). Pts with continue decline of TGFβ at cycle 5, approach the values of the healthy volunteers. None of them progressed. Updated results will be presented.
Citation Format: Garrone O, Tonissi F, Lingua D, Vandone AM, Vivenza D, Denaro N, Lo Nigro C, Merlano MC. The TRANSERI project: Effect of eribulin (E) in patients with metastatic breast cancer (mBC) on circulating TGFβ and TNFα. Relationship with outcome [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-04-01.