Abstract P5-11-04: Anti-proliferative effect of oral metronomic vinorelbine (mVNB) in PAM50 Luminal/HER2-negative early breast cancer (SOLTI-1501 VENTANA): A randomized, three-arm, window-of-opportunity study
Authors: Prat A , Adamo B , Pascual T , Perez Fidalgo JA , Blanch S , Martínez N , Gomez Pardo P , Lopez Gonzalez A , Murillo Jaso L , Amillano K , Vidal M , Paré L , Canes J , Galvan P , Gonzalez Farre B , Ortega Cebrián V , Gonzalez X , Bellet Ezquerra M , Villagrasa P , Ciruelos E 
Published: May 2019

Abstract
BACKGROUND: The anti-proliferative effect of mVNB alone or in combination with endocrine therapy in patients with hormone receptor-positive/HER2- breast cancer (BC) has been scarcely addressed.
METHODS: Postmenopausal women with untreated stage I-III BC were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5mg/day, oral mVNB 50mg 3 days/week or the combination. The 1ary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of mVNB+LTZ was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene Proliferation Score in each arm. 2ary objectives included safety and the comparison of the anti-proliferative effect between arms. An unplanned analysis of stromal tumor infiltrating lymphocytes (sTILs) was performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360TM panel. Changes in the expression of 790 genes/signatures tracking multiple biological processes from tumor cells and the microenvironment were evaluated within each arm using paired (surgery vs. baseline) univariate analyses. P-values were corrected for multiple comparisons using false discovery rate (FDR).
RESULTS: A total of 61 patients were randomized and 54 paired samples (89%) were analyzed. Main patient characteristics were mean age 67, mean tumor size 1.7 cm, stage I (55.7%) and grade 1-2 (90%). Grade 3 toxicities occurred in 3.3% of cases. Baseline samples were Luminal A (72.3%) or B (27.7%). The anti-proliferative effect of mVNB+LTZ (-73.2%) was superior to both monotherapy arms combined (-49.9%; p=0.001) and mVNB (-19.1%; p&lt;0.001). The anti-proliferative effect of mVNB+LTZ (-73.2%) was higher compared to LTZ (-65.7%) but did not reach statistical significance (p=0.328). Across the mVNB+LTZ, LTZ and VNB arms, 413 (52.3%), 403 (51.0%) and 21 (2.6%) genes/signatures were found differentially expressed (FDR&lt;5%) between baseline and surgery samples. Compared to mVNB+LTZ baseline samples, surgical samples showed higher expression of AP-1 transcription factor subunits FOS and JUN, inflammatory chemokines (e.g. CCL4 and IL6), stromal-related genes (e.g. CAV1 and stroma signature) and immune infiltration (e.g. CD8 T-cell signature) and lower expression of proliferation-related genes (e.g. MKI67 and UBE2C), estrogen receptor-signaling and Risk of Recurrence. Of the 413 genes found differentially expressed in surgical samples compared to baseline samples in the mVNB+LTZ arm, 108 (26.2%) were not found in the LTZ arm. Among them, high expression of LAG3, CD24, CD84 and CCR5. Under the microscope, sTILs (≥10% at week 3) were observed in 6.6% (mVNB), 15% (LTZ) and 26% (mVNB+LTZ) of the cases. In tumors with ≤10% TILs at baseline, an increase in TILs was observed following LTZ (p=0.049) and mVNB+LTZ (p=0.012).
CONCLUSIONS: mVNB is well-tolerated and presents antiproliferative activity alone and in combination with LTZ. The increase of activated CD8 T-cells or TILs observed with LTZ+mVNB opens the possibility of studying combinations with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or combinations is warranted.
Citation Format: Prat A, Adamo B, Pascual T, Perez Fidalgo JA, Blanch S, Martínez N, Gomez Pardo P, Lopez Gonzalez A, Murillo Jaso L, Amillano K, Vidal M, Paré L, Canes J, Galvan P, Gonzalez Farre B, Ortega Cebrián V, Gonzalez X, Bellet Ezquerra M, Villagrasa P, Ciruelos E. Anti-proliferative effect of oral metronomic vinorelbine (mVNB) in PAM50 Luminal/HER2-negative early breast cancer (SOLTI-1501 VENTANA): A randomized, three-arm, window-of-opportunity study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-04.