GSJ Journal Club
Essential Reading From the Sarcoma and GIST Peer-Reviewed Literature

The peer-reviewed articles summarized in this section were selected by the Editorial Board for their timeliness, importance, relevance, and potential impact on clinical practice or translational research. 

Use of liquid biopsies to monitor disease progression in a sarcoma patient: a case report. Namlos HM, Zaikova O, Bierkehagen B, et al. BMC Cancer. 2017 Jan 6;17(1):29. doi: 10.1186/s12885-016-2992-8.Summary: Recent technological advances make it possible to use blood plasma containing circulating cell-free tumor DNA (ctDNA) as a liquid biopsy. In this case report we show how serial liquid biopsies can be used to monitor the disease course and detect disease recurrence in a sarcoma patient. A 55-year-old male presented with a rapidly growing, painful palpable mass in the left groin region, and a biopsy revealed a high-grade malignant spindle cell sarcoma. No metastases were detected on radiologic imaging scans. Using targeted resequencing with a custom 900 cancer gene panel, eight somatic mutations among them KRAS and NF1, were identified in the primary tumor. Targeted resequencing of plasma cell-free DNA (ctDNA) collected before and after surgery and at disease progression confirmed the presence of six of eight mutations at all three time points. The ctDNA level, estimated from the somatic allele frequencies of these six mutations, was high in plasma taken at the time of surgery, at levels similar to the primary tumor. Detection of low levels of ctDNA three days after surgery indicated persistent microscopic disease. Repeated radiologic imaging six weeks postoperatively showed widespread metastatic disease in the lungs, skeleton and the pelvic region. At this time point there was a dramatic increase in the ctDNA level, reflecting the disease progression of the patient. The patient had an unusually aggressive cancer, and succumbed to the disease 13 weeks after surgery.
Conclusion: This case report demonstrated that targeted resequencing of ctDNA from longitudinal collected plasma can be used to monitor disease progression in a soft tissue sarcoma patient, including manifestation of metastatic disease. The ctDNA represented the genomic profile of the tumor, supporting clinical use of liquid biopsies to identify tumor-specific mutations as well as recurrent disease.

Response to anti-PD1 therapy with nivolumab in metastatic sarcomas. Paoluzzi L, Cacavio A, Ghesani M, et al. Clin Sarcoma Res. 2016;Dec. 30:66-24.
Summary: Manipulation of immune checkpoints such as CTLA4 or PD-1 with targeted antibodies has recently emerged as an effective anticancer strategy in multiple malignancies. Sarcomas are a heterogeneous group of diseases in need of more effective treatments. Different subtypes of soft tissue and bone sarcomas have been shown to express PD-1 ligand. This study retrospectively analyzed a cohort of patients (pts) with relapsed metastatic/unresectable sarcomas, who were treated with nivolumab provided under a patient assistance program from the manufacturer. Pts underwent CT or PET/CT imaging at baseline and after at least four doses of nivolumab; RECIST 1.1 criteria were used for response assessment. Twenty-eight pts with soft tissue (STS, N = 24) or bone sarcoma (N = 4), received IV nivolumab 3 mg/kg every 2 weeks from July 2015. Median age was 57 (24-78), male:female ratio was 14:14; the median number of nivolumab cycles was eight. Eighteen pts concomitantly received pazopanib at 400-800 mg daily. The most common side effect was grade 1-2 LFT elevations; grade 3-4 toxicity occurred in five patients (colitis, LFT elevations, pneumonitis). Twenty-four pts received at least four cycles. We observed three partial responses: one dedifferentiated chondrosarcoma, one epithelioid sarcoma and one maxillary osteosarcoma (last two patients on pazopanib); nine patients had stable disease including three leiomyosarcomas; 12 patients had progression of disease including 4 leiomyosarcoma. Clinical benefit (response + stability) was observed in 50% of the evaluable patients.
Conclusion: These data provide a rationale for further exploring the efficacy of nivolumab and other checkpoint inhibitors in soft tissue and bone sarcoma.

Trabectedin for soft tissue sarcoma: current status and future perspectives. Gordon EM, Sanhala KK, Chawla N, et al. Adv Ther. 2016;33:1055-10771.
Summary: Trabectedin, derived from the marine ascidian, Ecteinascidia turbinata, is a natural alkaloid with multiple complex mechanisms of action. On 23 October 2015, 15 years after the results of the first Phase 1 clinical trial using trabectedin for chemotherapy-resistant solid malignancies was reported, and 8 years after its approval in Europe, the United States Food and Drug Administration (USFDA) finally approved trabectedin for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma that has failed a prior anthracycline-containing regimen. Approval was based on the results of a pivotal Phase 3 trial involving a 2:1 randomization of 518 patients (who were further stratified by soft tissue sarcoma subtype), in which a significant improvement in progression-free survival was reported in the trabectedin-treated group vs. the dacarbazine-treated group (P < 0.001). In this trial, the most common adverse reactions were nausea, fatigue, vomiting, constipation, anorexia, diarrhea, peripheral edema, dyspnea, and headache, while the most serious were neutropenic sepsis, rhabdomyolysis, cardiomyopathy, hepatotoxicity, and extravasation leading to tissue necrosis. The most common grade 3-4 adverse events were laboratory abnormalities of myelosuppression in both arms and transient transaminitis in the trabectedin arm.
Conclusion: In a recent Phase 2 trial, trabectedin had a similar outcome as doxorubicin when given as a single agent in the first-line setting. Studies are also being conducted to expand the use of trabectedin not only as a first-line cancer drug, but also for a number of other clinical indications, for example, in the case of mesenchymal chondrosarcoma, for which trabectedin has been reported to be exceptionally active. The possibility of combining trabectedin with targeted therapies, immune checkpoint inhibitors or virotherapy would also be an interesting concept. In short, trabectedin is an old new drug with proven potential to impact the lives of patients with soft tissue sarcoma and other solid malignancies.

Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Tap WD, Jones RL, Van Tine BA, et al. Lancet. 2016;388:488-497.
Summary: Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumor activity in human sarcoma xenografts. The study assessed the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumor tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomization was dynamic and used the minimization randomization technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided level of 0.2 and statistical power of 0.8. This study was registered with, number NCT01185964.
Findings: 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, P=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 0.46, 0.30-0.71, P=0.0003). The objective response rate was 18.2% (9.8-29.6) with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin (p=0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 mg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 μg/mL (CV% 33.0) and from 123 μg/mL (CV% 31.2) to 156 μg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients).
Conclusion: This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11.8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma.

Clinical implications of repeated drug monitoring of imatinib in patients with metastatic gastrointestinal stromal tumour. Hompland I, Bruland OS, Ubhayasek-hera, et al. Clin Sarcoma Res. 2016;21;Dec. DOI:10 1186/s13569-016-0062-2.
Summary: Imatinib mesylate (IM) is the preferred treatment for the majority of patients with metastatic gastrointestinal stromal tumour (GIST). Low trough IM concentration (Cmin) values have been associated with poor clinical outcomes in GIST patients. However, there are few studies of repeated measurements of IM levels, and therapeutic drug monitoring is not yet a part of routine clinical practice. This study was conducted to reveal clinical scenarios where plasma concentration measurement of IM trough level (Cmin) is advantageous. Patients with advanced GIST receiving IM were included from January 2011 to April 2015. Heparin plasma was collected at each follow-up visit. Ninety-six samples from 24 patients were selected for IM concentration measurement. Associations between IM plasma concentration and clinical variables were analyzed by Students’ t test, univariate and multivariate linear regression analyses. The mean IM Cmin plasma concentrations for patients taking <400, 400 and >400 mg daily were 782, 1132 and 1665 ng/mL, respectively (P = 0.010). High IM Cmin levels were correlated with age, low body surface area, low hemoglobin concentration, low creatinine clearance, absence of liver metastasis and no prior gastric resection in univariate analysis. In multivariate analysis age, gastric resection and liver metastasis were included in the final model. Eight patients had disease progression during the study, and mean IM levels were significantly lower at time of progression compared to the previous measurement for the same patients (770 and 1223 ng/mL, respectively; P = 0.020).
Conclusion: The results do not support repeated monitoring of IM levels on a routine basis in all patients. However, results have revealed clinical scenarios where drug measurement could be beneficial, such as for patients who have undergone gastric resection, suspicion of non-compliance, subjectively reported side effects, in elderly patients and at the time of disease progression.

High nuclear expression of proteasome activator complex subunit 1 predicts poor survival in soft tissue leiomyosarcomas. Lou S, Cleven AHG, Baluff B, et al. Clin Sarcoma Res. 2016;6:17
Summary: Previous studies on high grade sarcomas using mass spectrometry imaging showed proteasome activator complex subunit 1 (PSME1) to be associated with poor survival in soft tissue sarcoma patients. PSME1 is involved in immunoproteasome assembly for generating tumor antigens presented by MHC class I molecules. In this study, we aimed to validate PSME1 as a prognostic biomarker in an independent and larger series of soft tissue sarcomas by immunohistochemistry. Tissue microarrays containing leiomyosarcomas (n = 34), myxofibrosarcomas (n = 14), undifferentiated pleomorphic sarcomas (n = 15), undifferentiated spindle cell sarcomas (n = 4), pleomorphic liposarcomas (n = 4), pleomorphic rhabdomyosarcomas (n = 2), and uterine leiomyomas (n = 7) were analyzed for protein expression of PSME1 using immunohistochemistry. Survival times were compared between high and low expression groups using Kaplan–Meier analysis. Cox regression models as multivariate analysis were performed to evaluate whether the associations were independent of other important clinical covariates. PSME1 expression was variable among soft tissue sarcomas. In leiomyosarcomas, high expression was associated with overall poor survival (P = 0.034), decreased metastasis-free survival (P = 0.002) and lower event-free survival (P = 0.007). Using multivariate analysis, the association between PSME1 expression and metastasis-free survival was still significant (P = 0.025) and independent of the histological grade.
Conclusion: High expression of PSME1 is associated with poor metastasis-free survival in soft tissue leiomyosarcoma patients, and might be used as an independent prognostic biomarker.  GSJ