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

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.</jats:p

Abstract P5-21-29: Moving from the CLEOPATRA study to real life: Preliminary results from the G.O.N.O. SUPER trial

Abstract Background: Around 20% of breast cancers (BC) are HER-2+. Trastuzumab (T) has dramatically changed the outcome of HER-2+ BC patients (pts), both in early and in advanced settings. The combination of Pertuzumab (P) plus T and docetaxel, used as first-line treatment for HER-2+ metastatic BC (MBC) in the phase III CLEOPATRA study, significantly prolonged progression free survival (PFS) and overall survival (OS). In order to verify the results of the Cleopatra trial in unselected pts, we performed a multicenter, retrospective-prospective, observational study, in HER-2+ MBC pts candidate to receive first line therapy with P plus T plus taxanes. Methods: We analyze the outcome of all HER-2+ MBC pts treated with P+T and taxanes, as first line therapy since the availability of P in Italy (2013), at 13 general and university hospitals. Results: Until June 6th data from 217 HER-2+ MBC pts were recorded. Main pts' characteristics were: median age 54 y (28-80), median ECOG PS 0 (0-2), hormonal receptor positive 152 pts (70%), 60 pts (27.6%) received neo/adjuvant chemotherapy (CT) + T and 75 pts (34.5%) adjuvant endocrine therapy. Most common metastatic sites: bone 121 pts (55.7%), liver 85 pts (39.2%), lung 61 pts (28.1%), soft tissues 133 pts (61.3%); 8 pts had CNS involvement. Seventy-eight pts (35.9%) had bone and/or soft tissues disease only; 108 pts (49.7%) had metastatic disease on presentation. Median number of metastatic sites was 3 (1-8). 144 pts (66.3%) and 72 pts (33.2%) received docetaxel (D) and paclitaxel (P) respectively. Median number of CT cycles was 6 for both drugs (D range 1-13; P range 1-18). Up to now 23 pts are still on CT and 86 on maintenance; ORR in evaluated pts (189) is 80.9% (47 and 106 pts obtained CR and PR respectively), 11 pts experienced PD during CT; 113 pts (58.2%) received endocrine therapy during maintenance.Median PFS is 14.7+ months (0.3+ - 53.2+). Most common adverse events are reported in table 1 Table 1Adverse EventAll grades N (%)Grade 3-4 N (%)Leukopenia39 (18)10 (4.6)Neutropenia42 (19.3)16 (7.3)Anemia50 (23)2 (0.9)Febrile Neutropenia7 (3.2) Diarrhea103 (47.4)10 (4.6)Asthenia127 (58.5)5 (2.3)Peripheral Neuropathy80 (36.8)3 (1.3)Stomatitis67 (30.8)2 (0.9) Nail changes, nausea, alopecia, rash and arthro-myalgia were also reported. Three pts interrupted CT due to symptomatic drop of left ventricular ejection fraction (LVEF); 2 pts interrupted maintenance P due to rash and dyspnea respectively, 16 stopped P and T due to drop in LVEF, 1 due to occurrence of ALL and 1 refused to continue. Conclusions: Our preliminary results highlight the activity and safety of the combination of CT plus P and T in unselected HER-2+ MBC patients. The study is ongoing and updated results will be presented. Citation Format: Garrone O, D'Onofrio L, Blondeaux E, Bertolini I, Giarratano T, Beano A, Saggia C, Cazzaniga M, LaVerde N, Collovà E, Milani A, De Conciliis E, Coltelli L, Airoldi M, Del Mastro L, Cursano MC, Michelotti A, Vandone AM, Guarneri V, Donadio M, Riva F, Nuzzo A, Merlano MC. Moving from the CLEOPATRA study to real life: Preliminary results from the G.O.N.O. SUPER trial [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 P5-21-29.</jats:p