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Influence of eribulin on proliferation, migration and invasion properties of leiomyosarcoma cell line models
abstracts
Annals of Oncology
GlaxoSmithKline. S. St. Laurent: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. S. Zheng: Full / Part-time employment: GlaxoSmithKline. H. StirnadelFarrant: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. C. Dharmani: Full / Part-time employment: GlaxoSmithKline.
1729P
Expenses: Eisai. A. Gallego Martınez: Travel / Accommodation / Expenses, Non-remunerated activity/ ies, training courses: Eisai. A. Redondo: Honoraria (self), Research grant / Funding (institution): Eisai. All other authors have declared no conflicts of interest.
Resection of high-grade large soft tissue sarcoma with adequate wide margin can lead to good local control without adjuvant radiotherapy
T. Kunisada, E. Nakata, J. Hasei, T. Ozaki Department of Orthopaedic Surgery, Okayama University Hospital, Okayama, Japan Background: Soft tissue sarcoma (STS) has been treated by achieving safe surgical margin rather than by using adjuvant radiotherapy (RT) in our country and 2-cm wide margin can be considered as adequate margin according to Kawaguchi’s criteria. We evaluated local recurrence (LR) and prognosis following resection of high-grade large STS using JOA surgical margin concept. Methods: Treatment strategy: Surgical resection with at least 2cm-wide margin was attempted whenever possible. Marginal or 1cm-wide margin are acceptable when preserving neurovascular bundles. RT is conducted postoperatively for marginal or R1 margin. Chemotherapy is indicated for patients less than 60 years old with deep seated, high grade and large tumor. PATIENTS: Inclusion criteria are localized STS in the extremities or trunk, larger than 5cm, FNCLCC grade 2 or 3, limb sparing surgery, primary complete resection at our institution, and minimum 3 years of follow-up. We retrospectively analyzed 69 patients treated between 2007 and 2014. Results: Median follow-up was 64 months. Median tumor size was 8.7cm. 6 patients underwent postoperative RT due to inadequate surgical margin. 21 (30%) patients received chemotherapy. There were 7 (10%) LR with average 14.5 months after surgery. Average size of tumor developing LR (14.8cm) was statistically larger than that without LR (9.8cm, p < 0.05). Only 1 of 9 patients developed LR after postoperative RT for inadequate resection. Distant metastasis was shown in 14 patients with average 20 months after surgery. There was no statistical difference of LR-free and overall survival between wide resection alone and inadequate resection with postoperative RT. Chemotherapy did not significantly affect overall survival. Conclusions: In this series of high-grade large STS, resection alone with 2cm-wide margin led to good local control, which is identical to previous reports with surgery plus RT. Adjuvant RT should be given for resection with marginal margin or R1 margin of the resected specimen. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
1730P
Methods: Eribulin was kindly provided by Eisai Inc. (Andover, USA) and tested on CP0024 and SK-UT-1 human LMS cell lines. Cellular proliferation was determined by SRB assay on 2D, and measured by spheroid diameter and by propidium iodide and calcein-AM double staining in 3D cultures by Celigo Platform (Nexcelom, Lawrence, USA).Cells were treated with increased concentrations of eribulin to determine IC50 values and its effect on proliferation. Chemotaxis and invasion were determined using transwell assay on 2D culture. Spheroids grown during 4 days were laid or embedded in matrigel for 3D assays and quantified over 3-7 additional days. Results: Both cell lines had a mesenchymal-like appearance on monolayer culture, although SK-UT-1 had a more compact spheroid pattern compared to CP0024. Proliferation, migration, and invasion were examined after exposure to eribulin. The results showed that eribulin is active on both cell lines inhibiting proliferation in 2 and 3D culture conditions at concentrations below the nanomolar range. Moreover, eribulin significantly inhibited migration and invasion. To our knowledge, these findings are the first to demonstrate the effect of eribulin in LMS cell line 3D models. Conclusions: Our results support the in vitro activity of eribulin in LMS cell lines and its further exploration as an agent with clinical benefit in patients with LMS. Legal entity responsible for the study: The authors. Funding: Eisai. Disclosure: M. Mendiola: Research grant / Funding (institution), Travel / Accommodation /
Influence of eribulin on proliferation, migration and invasion properties of leiomyosarcoma cell line models
M. Mendiola1, V. Heredia-Soto1, J. Escudero1, R. Crespo1, P. Ruiz1, A. Gallego Martınez2, on3, E. Ortiz-Cruz4, D. Bernabeu5, A. Redondo2 V. Martınez-Marin2, J.J. Pozo3, A. Berj 1 Oncologıa Traslacional, Instituto de investigaci on del Hospital Universitario La Paz, IdiPAZ, Madrid, Spain, 2Dept. Oncologia Medica, Hospital Universitario La Paz, Madrid, 3 ogica, Hospital Universitario La Paz, Madrid, Spain, 4Dept. Spain, Dept. Anatomıa Patol Cirugıa Ortope´dica, Hospital Universitario La Paz, Madrid, Spain, 5Dept. Radiologıa, Hospital Universitario La Paz, Madrid, Spain
1731TiP
EREMISS: Efficacy of regorafenib (REG) as maintenance therapy in non-adipocytic soft tissue sarcomas (STS) having received 1st-line doxorubicin-based chemotherapy (Doxo-CT)
N. Penel1, J-Y. Blay2, J. Wallet3, A. Le Cesne4, A. Italiano5, O. Mir4, S. Taieb6, M. Vanseymortier7, P. Desmet7, E. Decoupigny7, J. Courtial7, M.C. Le Deley7 1 General Oncology Department, Centre Oscar Lambret, Lille, France, 2Medicine, Centre Le´on Be´rard, Lyon, France, 3Biostatistics, Centre Oscar Lambret, Lille, France, 4 De´partement de Me´decine Oncologique, Institut Gustave Roussy, Villejuif, France, 5 Early Phase Trials Unit, Institute Bergonie´, Bordeaux, France, 6Imagerie, Centre Oscar Lambret, Lille, France, 7Clinical Research and Methodological Platform, Centre Oscar Lambret, Lille, France Background: In advanced STS, median progression-free survival (PFS) remains at 4 months (mo) and median overall survival (OS) is about 12-18 mo after Doxo-CT. There is currently no maintenance therapy available. A phase III trial has shown a modest benefit of a maintenance with ridafolimus compared to placebo (PBO) (PFS, 17.7 vs 14.6 weeks, HR ¼ 0.72). REG is an orally bioavailable multikinase inhibitor with meaningful activity in doxorubicin-refractory non-adipocytic STS. In a prior randomized phase II trial (REGOSARC; NCT01900743), median PFS was 4.0 mo with REG compared to 1.0 with PBO (HR ¼ 0.36, p < 0.0001) and median OS was 13.4 vs 9.0 mo (HR ¼ 0.67; p ¼ 0.059). Trial design: EREMISS (NCT03793361) is a multicenter (17 centers from the French Sarcoma Group) double-blind controlled randomized phase II trial assessing efficacy and safety of REG compared to PBO as maintenance therapy in metastatic / locally advanced STS experiencing stable disease (SD) or partial response (PR) after 6 cycles of Doxo-CT as 1st-line. The primary endpoint is PFS (RECIST 1.1, centrally reviewed). Secondary endpoints are efficacy (OS, Objective response, time to start subsequent therapy), safety and benefit/risk ratio (Q-TWIST). The randomization is balanced 1:1 and controlled for histology (leiomyosarcoma/synovial sarcoma/other sarcoma), response to CT (SD/PR) and centers. Pts receive either REG (120 mg/d 21/28 days) or PBO until unacceptable toxicity, progression or consent withdrawal. There is no crossover in this trial. Main eligibility criteria are: age 18; histologically-proven non-adipocytic STS, metastatic / locally advanced STS not amenable to curative intent surgery, PS < 2, measurable disease, SD or PR after 6 cycles of Doxo-CT. Based on the following assumptions: PFS, 7 (REG) vs 4 mo (PBO), HR ¼ 0.57, 1-sided a ¼ 5% and b ¼ 10%, the required number of events is 110 and the sample size is 126 pts. The planned study duration is 30 months. Enrolment is open since 12/2018. Clinical trial identification: NCT03793361. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: A. Le Cesne: Honoraria (self): PharmaMar; Honoraria (self): Lilly; Honoraria (self): Novartis. All other authors have declared no conflicts of interest.
Background: Eribulin has an effect on proliferation, migration and invasion of sarcoma and breast cancer in vitro assays. A phase III clinical trial in patients with advanced liposarcoma (LPS) or leiomyosarcoma (LMS) showed an improvement in overall survival (OS) for the eribulin arm compared to dacarbazine, although no benefit was observed in the LMS restricted subgroup. Based on these results, eribulin was approved only for advanced LPS patients. The aim of the current study is to evaluate the effect of eribulin on key cell properties, like proliferation, migration, and invasion in LMS cell lines, in conventional 2D, but also 3D culture models.
Volume 30 | Supplement 5 | October 2019
doi:10.1093/annonc/mdz283 | v707
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz283.063/5577518 by guest on 22 October 2019
Results: In the EU28 countries in 2019, there will be an estimated 993 incident cases of SS, 3,550 prevalent patients and 520 deaths. Most (74%) of the prevalent patients with SS will be 20-64 years old, and only 17% will be 65 years and older. Approximately 40% of patients newly diagnosed with SS will be of ages 20-44 years, and 32% of ages 45-64 years. There will be a low occurrence (<10%) of SS in the pediatric population ages 019 years, but more frequent in males for this age group. The incidence and prevalence of SS will not vary between males and females. However, the estimated mortality among adults will be higher in males than females. Accounting for the differences in incidence, among the pediatric SS patients, the mortality in females will be higher than males. 73% of the SS mortality in 2019 will be observed in 20-64 year old patients. Conclusions: SS is a rare disease. Life expectancy of patients with SS is lower than the general population in EU28 due to high mortality in the 20-64 year age group. SS also occurs among children. Population-based studies are needed to better characterize SS patient population for improving patient care and survival in EU28. Legal entity responsible for the study: The authors. Funding: GlaxoSmithKline. Disclosure: N. Joseph: Shareholder / Stockholder / Stock options, Full / Part-time employment:
Annals of Oncology
GlaxoSmithKline. S. St. Laurent: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. S. Zheng: Full / Part-time employment: GlaxoSmithKline. H. StirnadelFarrant: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. C. Dharmani: Full / Part-time employment: GlaxoSmithKline.
1729P
Expenses: Eisai. A. Gallego Martınez: Travel / Accommodation / Expenses, Non-remunerated activity/ ies, training courses: Eisai. A. Redondo: Honoraria (self), Research grant / Funding (institution): Eisai. All other authors have declared no conflicts of interest.
Resection of high-grade large soft tissue sarcoma with adequate wide margin can lead to good local control without adjuvant radiotherapy
T. Kunisada, E. Nakata, J. Hasei, T. Ozaki Department of Orthopaedic Surgery, Okayama University Hospital, Okayama, Japan Background: Soft tissue sarcoma (STS) has been treated by achieving safe surgical margin rather than by using adjuvant radiotherapy (RT) in our country and 2-cm wide margin can be considered as adequate margin according to Kawaguchi’s criteria. We evaluated local recurrence (LR) and prognosis following resection of high-grade large STS using JOA surgical margin concept. Methods: Treatment strategy: Surgical resection with at least 2cm-wide margin was attempted whenever possible. Marginal or 1cm-wide margin are acceptable when preserving neurovascular bundles. RT is conducted postoperatively for marginal or R1 margin. Chemotherapy is indicated for patients less than 60 years old with deep seated, high grade and large tumor. PATIENTS: Inclusion criteria are localized STS in the extremities or trunk, larger than 5cm, FNCLCC grade 2 or 3, limb sparing surgery, primary complete resection at our institution, and minimum 3 years of follow-up. We retrospectively analyzed 69 patients treated between 2007 and 2014. Results: Median follow-up was 64 months. Median tumor size was 8.7cm. 6 patients underwent postoperative RT due to inadequate surgical margin. 21 (30%) patients received chemotherapy. There were 7 (10%) LR with average 14.5 months after surgery. Average size of tumor developing LR (14.8cm) was statistically larger than that without LR (9.8cm, p < 0.05). Only 1 of 9 patients developed LR after postoperative RT for inadequate resection. Distant metastasis was shown in 14 patients with average 20 months after surgery. There was no statistical difference of LR-free and overall survival between wide resection alone and inadequate resection with postoperative RT. Chemotherapy did not significantly affect overall survival. Conclusions: In this series of high-grade large STS, resection alone with 2cm-wide margin led to good local control, which is identical to previous reports with surgery plus RT. Adjuvant RT should be given for resection with marginal margin or R1 margin of the resected specimen. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
1730P
Methods: Eribulin was kindly provided by Eisai Inc. (Andover, USA) and tested on CP0024 and SK-UT-1 human LMS cell lines. Cellular proliferation was determined by SRB assay on 2D, and measured by spheroid diameter and by propidium iodide and calcein-AM double staining in 3D cultures by Celigo Platform (Nexcelom, Lawrence, USA).Cells were treated with increased concentrations of eribulin to determine IC50 values and its effect on proliferation. Chemotaxis and invasion were determined using transwell assay on 2D culture. Spheroids grown during 4 days were laid or embedded in matrigel for 3D assays and quantified over 3-7 additional days. Results: Both cell lines had a mesenchymal-like appearance on monolayer culture, although SK-UT-1 had a more compact spheroid pattern compared to CP0024. Proliferation, migration, and invasion were examined after exposure to eribulin. The results showed that eribulin is active on both cell lines inhibiting proliferation in 2 and 3D culture conditions at concentrations below the nanomolar range. Moreover, eribulin significantly inhibited migration and invasion. To our knowledge, these findings are the first to demonstrate the effect of eribulin in LMS cell line 3D models. Conclusions: Our results support the in vitro activity of eribulin in LMS cell lines and its further exploration as an agent with clinical benefit in patients with LMS. Legal entity responsible for the study: The authors. Funding: Eisai. Disclosure: M. Mendiola: Research grant / Funding (institution), Travel / Accommodation /
Influence of eribulin on proliferation, migration and invasion properties of leiomyosarcoma cell line models
M. Mendiola1, V. Heredia-Soto1, J. Escudero1, R. Crespo1, P. Ruiz1, A. Gallego Martınez2, on3, E. Ortiz-Cruz4, D. Bernabeu5, A. Redondo2 V. Martınez-Marin2, J.J. Pozo3, A. Berj 1 Oncologıa Traslacional, Instituto de investigaci on del Hospital Universitario La Paz, IdiPAZ, Madrid, Spain, 2Dept. Oncologia Medica, Hospital Universitario La Paz, Madrid, 3 ogica, Hospital Universitario La Paz, Madrid, Spain, 4Dept. Spain, Dept. Anatomıa Patol Cirugıa Ortope´dica, Hospital Universitario La Paz, Madrid, Spain, 5Dept. Radiologıa, Hospital Universitario La Paz, Madrid, Spain
1731TiP
EREMISS: Efficacy of regorafenib (REG) as maintenance therapy in non-adipocytic soft tissue sarcomas (STS) having received 1st-line doxorubicin-based chemotherapy (Doxo-CT)
N. Penel1, J-Y. Blay2, J. Wallet3, A. Le Cesne4, A. Italiano5, O. Mir4, S. Taieb6, M. Vanseymortier7, P. Desmet7, E. Decoupigny7, J. Courtial7, M.C. Le Deley7 1 General Oncology Department, Centre Oscar Lambret, Lille, France, 2Medicine, Centre Le´on Be´rard, Lyon, France, 3Biostatistics, Centre Oscar Lambret, Lille, France, 4 De´partement de Me´decine Oncologique, Institut Gustave Roussy, Villejuif, France, 5 Early Phase Trials Unit, Institute Bergonie´, Bordeaux, France, 6Imagerie, Centre Oscar Lambret, Lille, France, 7Clinical Research and Methodological Platform, Centre Oscar Lambret, Lille, France Background: In advanced STS, median progression-free survival (PFS) remains at 4 months (mo) and median overall survival (OS) is about 12-18 mo after Doxo-CT. There is currently no maintenance therapy available. A phase III trial has shown a modest benefit of a maintenance with ridafolimus compared to placebo (PBO) (PFS, 17.7 vs 14.6 weeks, HR ¼ 0.72). REG is an orally bioavailable multikinase inhibitor with meaningful activity in doxorubicin-refractory non-adipocytic STS. In a prior randomized phase II trial (REGOSARC; NCT01900743), median PFS was 4.0 mo with REG compared to 1.0 with PBO (HR ¼ 0.36, p < 0.0001) and median OS was 13.4 vs 9.0 mo (HR ¼ 0.67; p ¼ 0.059). Trial design: EREMISS (NCT03793361) is a multicenter (17 centers from the French Sarcoma Group) double-blind controlled randomized phase II trial assessing efficacy and safety of REG compared to PBO as maintenance therapy in metastatic / locally advanced STS experiencing stable disease (SD) or partial response (PR) after 6 cycles of Doxo-CT as 1st-line. The primary endpoint is PFS (RECIST 1.1, centrally reviewed). Secondary endpoints are efficacy (OS, Objective response, time to start subsequent therapy), safety and benefit/risk ratio (Q-TWIST). The randomization is balanced 1:1 and controlled for histology (leiomyosarcoma/synovial sarcoma/other sarcoma), response to CT (SD/PR) and centers. Pts receive either REG (120 mg/d 21/28 days) or PBO until unacceptable toxicity, progression or consent withdrawal. There is no crossover in this trial. Main eligibility criteria are: age 18; histologically-proven non-adipocytic STS, metastatic / locally advanced STS not amenable to curative intent surgery, PS < 2, measurable disease, SD or PR after 6 cycles of Doxo-CT. Based on the following assumptions: PFS, 7 (REG) vs 4 mo (PBO), HR ¼ 0.57, 1-sided a ¼ 5% and b ¼ 10%, the required number of events is 110 and the sample size is 126 pts. The planned study duration is 30 months. Enrolment is open since 12/2018. Clinical trial identification: NCT03793361. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: A. Le Cesne: Honoraria (self): PharmaMar; Honoraria (self): Lilly; Honoraria (self): Novartis. All other authors have declared no conflicts of interest.
Background: Eribulin has an effect on proliferation, migration and invasion of sarcoma and breast cancer in vitro assays. A phase III clinical trial in patients with advanced liposarcoma (LPS) or leiomyosarcoma (LMS) showed an improvement in overall survival (OS) for the eribulin arm compared to dacarbazine, although no benefit was observed in the LMS restricted subgroup. Based on these results, eribulin was approved only for advanced LPS patients. The aim of the current study is to evaluate the effect of eribulin on key cell properties, like proliferation, migration, and invasion in LMS cell lines, in conventional 2D, but also 3D culture models.
Volume 30 | Supplement 5 | October 2019
doi:10.1093/annonc/mdz283 | v707
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz283.063/5577518 by guest on 22 October 2019
Results: In the EU28 countries in 2019, there will be an estimated 993 incident cases of SS, 3,550 prevalent patients and 520 deaths. Most (74%) of the prevalent patients with SS will be 20-64 years old, and only 17% will be 65 years and older. Approximately 40% of patients newly diagnosed with SS will be of ages 20-44 years, and 32% of ages 45-64 years. There will be a low occurrence (<10%) of SS in the pediatric population ages 019 years, but more frequent in males for this age group. The incidence and prevalence of SS will not vary between males and females. However, the estimated mortality among adults will be higher in males than females. Accounting for the differences in incidence, among the pediatric SS patients, the mortality in females will be higher than males. 73% of the SS mortality in 2019 will be observed in 20-64 year old patients. Conclusions: SS is a rare disease. Life expectancy of patients with SS is lower than the general population in EU28 due to high mortality in the 20-64 year age group. SS also occurs among children. Population-based studies are needed to better characterize SS patient population for improving patient care and survival in EU28. Legal entity responsible for the study: The authors. Funding: GlaxoSmithKline. Disclosure: N. Joseph: Shareholder / Stockholder / Stock options, Full / Part-time employment: