Treatment Of Soft Tissue Sarcomas Research Articles

Clinical Outcomes After Definitive Treatment of Soft Tissue Sarcoma of the Hand: A Retrospective Cohort Study of 109 Patients

The purpose of this study was to provide updated data on oncologic outcomes following definitive surgical treatment of soft tissue sarcoma of the hand in a cohort of 109 patients, as well as to characterize risk factors for poor oncologic and functional outcomes. We analyzed data from 109 consecutive patients who had definitive surgical treatment for soft tissue sarcoma of the hand performed between 1996 and 2019 by a single surgeon at a sarcoma center. Primary outcomes included functional outcome (assessed by Musculoskeletal Tumor Society scores), disease-free survival (DFS), and overall survival (OS). We compiled descriptive data and used a multivariable linear model to identify factors associated with functional outcomes. Kaplan-Meier methods were used to estimate 5- and 10-year DFS and OS. Patients had a median age of 36 years at presentation. Median follow-up was 6.1 years among patients alive at the end of follow-up. The median Musculoskeletal Tumor Society score was 29; functional outcome was worse among patients with high-grade tumors or complications. Among the 107 patients who became disease-free, there were four local recurrences (one with metastasis), six distant recurrences, and one death without recurrence. All local recurrences were deep tumors (two myxofibrosarcoma and two myxoinflammatory fibrosarcoma). Estimated 5- and 10-year DFS rates were 89% (95% confidence interval [CI]: 83% to 96%) and 88% (95% CI: 80% to 95%). There were seven deaths, and the estimated 5- and 10-year OS rates were 95% (95% CI: 90% to 100%) and 92% (95% CI: 84% to 100%). Larger tumor size and higher stage at diagnosis were associated with shorter DFS and OS in univariable analyses; low event rates precluded multivariable analysis of survival. Aggressive disease-specific surgical and multidisciplinary treatment can yield long DFS and OS, and good functional outcomes. However, complications and high-grade tumors are associated with worse functional scores. Prognostic II.

Correlation of ctDNA and LDH levels in patients with soft tissue sarcoma: A single-center experience.

e23535 Background: Our study aims to examine the relationship between the presence of circulating tumor DNA (ctDNA) and lactate dehydrogenase (LDH) in patients diagnosed with soft tissue sarcoma (STS). There is emerging yet limited data on the applicability of ctDNA in STS. LDH is a cheaper readily available test that has been associated with unfavorable overall survival in different malignancies. This research aims to understand the correlation between ctDNA and LDH as a tool to assess its utility as indirect markers of response to treatment in STS. Methods: This was a single-center retrospective chart review on patients diagnosed with STS. Eligibility criteria included a confirmed diagnosis and available measurements of both ctDNA and LDH levels. Correlation was compared between Non-hispanic whites (NHW) and Hispanics (H). Data was sourced from our electronic medical record and Signatera™ assay to obtain the primary endpoints. Specimens were standardized in accordance to Natera’s™ specifications. Study endpoints included the correlation coefficients between ctDNA and LDH levels. A two-stage study design was applied for a robust analysis. Spearman's rank correlation coefficient (denoted as r) was employed for statistical analysis, assessing the strength and direction of the monotonic relationship between ctDNA and LDH levels. Marker values were treated as continuous variables in these analyses. All analyses were executed in GraphPad Prism software. Results: The cohort comprised 33 patients with STS (14 NHW, 19 H). The median LDH in H was 189 (interquartile range (IQR) = 184) vs 184 (IQR = 105) in NHW. Comparatively, the median ctDNA in H was 0 (IQR = 39.3) and also 0 (IQR = 11.1) in NHW. The overall correlation between ctDNA and LDH levels was moderate positive (r = 0.5, p = 0.002), indicating a consistent, though not necessarily linear, relationship. Subgroup analysis showed r = 0.19 (p = 0.52) in NHW and r = 0.43 (p = 0.1) in H groups, suggesting ethnic variability in the ctDNA-LDH correlation. These findings were statistically significant within the predefined confidence limits and probability values. Conclusions: Our study demonstrated a significant correlation between ctDNA levels and LDH in STS patients, implying that higher ctDNA may be associated with higher LDH levels. This association can lead clinicians in monitoring LDH more frequently as an indirect marker of response to treatment in STS. This correlation suggests an increased tumor burden with a higher inflammatory response, with variations across different racial groups. The wider availability of LDH testing compared to ctDNA in many centers highlights LDH's potential as an indirect marker for STS. Further research with larger prospective cohorts is essential to confirm LDH's role paired with ctDNA in guiding treatment decisions in STS, enhancing its utility in clinical practice.

Assessing response and adherence to neoadjuvant treatment in soft tissue sarcomas of the extremities.

e23559 Background: The standard treatment for large, intermediate, and high-grade extremity soft tissue sarcoma (ESTS) involves surgery and radiotherapy. The addition of chemotherapy has improved oncological outcomes, such as reduced recurrence and prolonged survival. However, the relationship between neoadjuvant treatment and tumor response in ESTS is not well understood. Pathological evaluation of viable tumor cells after treatment is an indicator of tumor response, yet the proportion of viable tumor cells remains high, particularly in high-risk sarcomas. Combining radiotherapy with chemotherapy may enhance the response of tumor cells. Objective: This study aims to evaluate the effects of neoadjuvant chemotherapy (NCT) and chemoradiotherapy (CRT) on patients with high-risk ESTS and to determine its impact on the pathological response. Methods: We enrolled adult patients with high-risk ESTS (SARCULATOR OS < 60%) at a single center in Latin America. The study was designed to analyze the pathological response in patients with high-risk sarcomas who underwent neoadjuvant CRT and resection and to correlate these responses with various variables. The treatment response was evaluated using the EORTC–STBSG criteria. Results: Thirty-four patients were recruited, with a median age of 44 years (IQR 23-74). Fifty-two percent had T3 tumors (mean size 18 cm), and 79.4% were diagnosed at stage III. The predominant histological subtypes were synovial sarcoma (35.3%) and dedifferentiated liposarcoma (29.4%). The most used NCT regimen was doxorubicin/ifosfamide (84.4%), with 62.5% receiving a dosage intensity of Q4W, affected by overcapacity, and 25% received Q3W. Concurrent CRT was administered to 64.7% of patients, with a median delay to onset of 36 days due to overcapacity (43.5%). Only 79.4% completed three preoperative cycles of treatment. As for the response, 41.2% had an EORTC-E response, and 17.6% had an EORTC-D response. Grade 3 neutropenia and anemia occurred in 17.2% and 8.8% of patients, respectively. Disease progression during NCT was observed in six patients. No significant difference was found in the pathological response between the Q4W and Q3W dosage intensities (p = 0.62). Conclusions: The impact of NCT on pathological responses was not significantly high, which may be due to the predominant histological type in our series. The main cause of treatment delay at our center was due to overcapacity; however, this did not influence the pathological response relative to dose intensity. Additional follow-up assessments are required to determine the influence on relapse-free and overall survival based on the response after preoperative CRT.

A phase I/II trial of neoadjuvant pegylated arginine deiminase (ADI-PEG 20) with ifosfamide and radiotherapy in soft tissue sarcomas (STS) of the trunk or extremity.

TPS11591 Background: Outcomes for the treatment of metastatic STS remain poor. Better therapies are needed for local and distant control. Arginine is essential to neoplastic growth, yet up to 88% of STS do not express argininosuccinate synthetase (ASS1), an enzyme necessary to produce arginine. ADI-PEG 20 is a microbial enzyme that degrades arginine causing auxotrophy in cancer cells that are ASS1 negative. Pre-clinical data demonstrates that arginine deprivation shunts glutamine towards oxidation via the TCA cycle, thus depleting glutathione stores and increasing oxidative stress to the cell. We hypothesize that the combination of ADI-PEG 20, ifosfamide, and radiation therapy can potentiate cellular death. The encouraging safety and clinical data from the ADI-PEG 20 + radiation + temozolomide trial (NCT04587830) further support this combination. We are conducting a phase I/II trial examining the safety and tolerability to determine the recommended phase II dose (R2PD) and evaluate the efficacy of ADI-PEG 20 in combination with ifosfamide and radiation in patients with high-grade STS. Methods: Eligible patients include untreated intermediate or high-grade extremity or truncal STS planned for definitive resection with performance status 0-1 and adequate organ function. Metastatic disease is exclusionary as well as receiving prior treatment for the study cancer. The total number of patients to be enrolled is approximately 35. Up to 15 patients will be enrolled in the phase I portion with a 3 + 3 dose escalation design with ADI-PEG 20 in combination with escalating doses of ifosfamide and radiation. The primary objectives include determining safety and tolerability as well as the recommended phase II dose (RP2D). Patients will be treated neoadjuvantly with ADI-PEG 20 dosed once weekly starting on Cycle 1 Day -7 with ifosfamide for up to three cycles in combination with standard radiotherapy given over approximately 5 weeks. Ifosfamide will be administered on Days 1 - 5 of all 3 cycles. The phase II participants will receive the combination with ifosfamide at the RP2D determined during phase I. The primary objective of the phase II portion is to determine the percent necrosis and pathologic complete response (pCR) at the time of resection. These endpoints will be summarized by proportions along with the associated 2-sided exact 95% CIs. Assuming the true pCR rate is 25%, enrolling 20 patients will result in a 90% CI for estimating the pCR (10%, 45%). The trial has begun accrual and is soon to open at multiple sites. Clinical trial information: NCT05813327 .

The efficacy of immune checkpoint inhibitors as a part of multimodality treatment in soft tissue and bone sarcoma in an academic community setting.

e23564 Background: Prior studies have shown response to immune checkpoint inhibitors (ICI) in a variety of sarcoma subtypes, however, much is still unknown about ICI use in specific sarcoma subtypes due to disease rarity. Patients (pts) are often treated with these agents as part of clinical trials, and real world data in the community setting is lacking. The aim of this study is to report real world efficacy and safety of ICI in sarcoma either alone or with radiation (RT) and/or surgery. Methods: A retrospective cohort review was conducted to identify pts with soft tissue and bone sarcoma who were administered ICI at Kellogg Cancer Center at NorthShore University HealthSystem/Endeavor Health. Pts who received ICI as part of a clinical trial were excluded. Results: A total of 29 pts receiving ICI were identified. Pts had a median of 1 prior systemic therapy. ICI included pembrolizumab (n = 23), nivolumab (n = 5), and ipilimumab/nivolumab (n = 1). Treatment was discontinued in 28 pts due to disease progression (n = 18), toxicities (n = 3), death (n = 2), and maximal response (n = 5). One patient is still undergoing treatment. Median progression-free survival (PFS) was 4.9 months. Median overall survival (OS) was 14 months. Overall response rate (ORR) is 31%. Median duration of response was not reached (44+ months). Complete response (CR) (n = 5) reported in 3 pts with undifferentiated pleomorphic sarcoma (UPS), 1 pt with SMARCA4 deficient undifferentiated sarcoma, and 1 pt with dedifferentiated chondrosarcoma. Partial response (PR) (n = 4) reported in 1 pt with UPS, 1 pt with dedifferentiated liposarcoma, 1 pt with high grade spindle sarcoma of bone, and 1 pt with malignant peripheral nerve sheath tumor. Of those pts with a CR, 2 patients received only pembrolizumab, 1 pt was administered concomitant RT, and 2 pts had administered concomitant surgery. Of the pts who had PR, 3 were also treated with concomitant RT. Grade 3 immune related adverse effects were reported in 5 of the 29 patients. Of these patients, 2 had documented CR and 3 documented PR. Conclusions: This study expands on the real world efficacy of ICI in a variety of sarcoma subtypes. CR and PR rates in this setting were high, and responses were durable, although selection bias for treatment may have played a role. This data supports the treatment of metastatic sarcoma with ICI, especially with concomitant RT and surgery, in a variety of subtypes.

Fragility index analysis of systemic therapy clinical trials in soft tissue sarcoma (STS).

11581 Background: The fragility index (FI) measures the robustness of randomized clinical trials (RCT) that have positive results based on statistical p-values. It estimates the minimum number of events that are needed to reverse the trial results from positive to negative. Here, we perform FI analysis on RCTs evaluating systemic treatments for STS. Methods: A systematic search of the Medline and Embase databases for RCTs in adults with advanced STS (Jan 1998 to Dec 2023) was conducted. Gastrointestinal stromal tumor trials were excluded. The FI framework was adapted to allow the use of time-to-event (TTE) outcomes – progression-free survival (PFS) or overall survival (OS) as previously described (Desnoyers et al 2021). Survival tables were reconstructed from published data on positive TTE outcomes, using the Parmar Toolkit. Positive secondary endpoints were used only if the primary endpoint was negative. The number of additional events that would result in a non-significant effect for the hazard ratio (HR) of the positive endpoint of each trial (FI) was calculated and expressed as a proportion of the size of the experimental arm (fragility quotient; FQ). The number of censored patients – those who withdrew consent or were lost to follow-up (Cn) was noted. Results: Among 47 RCTs, 16 (8 phase II; 8 phase III) trials had positive outcomes. The primary endpoint was positive and used for FI analysis in 11/16 trials (68.8%). PFS was the most common positive outcome, evaluated in 13 trials (81.3%). The median FI was 6 (range 2 – 52), with FI < 10 observed in 11 trials (68.8%). Median FQ was 7% (range 1 – 59%) and 10 trials (62.5%) had FQ < 10%. Among 14 trials that reported data, Cn was ≥ FI in 7 trials (50%). Only 2 of 4 trials (50%) that led to regulatory approval had FI > 10 or FQ > 10%. Of the other 2, one drug approval was subsequently withdrawn (Table). Conclusions: Most positive clinical trials in STS were fragile and their outcomes may be confounded by the level of censoring. Real-world evaluation of approved systemic therapies and value scales such as ESMO Magnitude of Clinical Benefit scale or ASCO value framework are needed to confirm clinical benefit of systemic treatments in STS.[Table: see text]

Differences in baseline ctDNA value between Hispanic and non-Hispanic White patients with soft tissue sarcoma (STS): A single-center retrospective analysis.

e23533 Background: Circulating tumor DNA (ctDNA) has shown promise as a biomarker for cancer detection and tracking in multiple malignancies like melanoma, colon and lung. Due to the heterogeneity of sarcoma, there has been limited research on ctDNA as a tool for measuring minimal residual disease (MRD). Differences in baseline in ctDNA for STS in racial minorities have been poorly studied. To identify potential racial differences in the efficacy of this tool, this study compares the quantitative values of baseline ctDNA between non-Hispanic white (NHW) and Hispanic (H) patients with soft tissue sarcoma (STS). Methods: The medical records of 33 STS patients who had ctDNA analysis from Natera™ were examined retrospectively at Dignity Health Cancer Institute.There were 19 H patients and 14 NHW patients in the group. All Black (B), Asian (A), and Other (O) racial groups were excluded due to lower numbers. GraphPad Prism software was used to examine the baseline ctDNA levels. Using continuous measures for statistical analysis, we conducted descriptive statistics and determined the mean, standard deviation, and median ctDNA levels for each group. The ctDNA levels were compared between groups using a two-tailed t-test with a significance level of p < 0.05. Results: The average ctDNA levels were 416.675 (standard deviation = 1349.394) in NHW and 300.305 (standard deviation = 1000.543) in H. The median levels were 0 for both groups. The statistical analysis showed that there was no significant differences in the baseline ctDNA levels between the two groups (p = 0.73). Furthermore, the gender distribution among NHW and Hs in the cohort was comparable, with a p-value of 1.00. Conclusions: This study establishes that there is no substantial differences in baseline levels of ctDNA between H and NHW patients with STS. These findings indicate that ctDNA levels in these populations can be equally utilized for diagnostic and monitoring reasons in clinical settings. Nevertheless, to gain a comprehensive understanding of the racial disparities in ctDNA utility and its implications in customized treatment for STS, it is necessary to conduct more extensive research with larger sample sizes and incorporate additional variables.

Pathologic complete response in patients with localized soft tissue sarcoma treated with neoadjuvant therapy and its correlation with clinical outcomes: A systematic review.

e23529 Background: Soft tissue sarcomas (STS), comprising approximately 1% of adult solid malignancies, are primarily treated with surgery, with the choice of perioperative treatment being a challenging and highly individualized decision. Clinical trials assessing neoadjuvant modalities in STS predominantly use clinical outcomes or radiologic response as endpoints, with pathologic complete response (pCR) typically not being employed as a designated study endpoint. There is a growing inclination towards neoadjuvant treatment for STS. While pCR serves as a crucial marker guiding treatment decisions in other neoplasms like breast cancer and urothelial cancer, it is not yet used in a similar setting for STS. Our systematic review aimed to assess the rates of pCR in clinical trials of different neoadjuvant modalities for STS and its correlation with patient clinical outcomes. Methods: A systematic literature search was conducted, with eligibility criteria being prospective or retrospective, phase I, II or III trials testing neoadjuvant treatments for STS. Neoadjuvant treatments were chemotherapy, radiotherapy, TKIs or combinations of the above. 23 studies were included, from which data regarding rates of pCR with each treatment, as well as the correlation of pCR with clinical outcomes, were retrieved. Results: Of the 23 trials included, seven did not assess pCR. In the remaining 16 trials, pCR was defined by either ≥90% or ≥95% pathologic necrosis in the tumor specimen. The percentage of patients who achieved pCR ranged from 8 to 58%. Most of these trials did not assess an association between pCR and clinical outcomes. However, among those investigating this correlation, a positive association was identified between pCR and both 5-year disease-specific survival (DSS) and 5-year overall survival (OS). Table 1 summarizes the eight trials that sought to correlate rates of pCR with clinical outcomes. Conclusions: Our findings indicate pCR variability across different neoadjuvant treatments for STS and a possible positive correlation with patient outcomes. Consequently, we propose considering pCR as a surrogate endpoint in future prospective trials for STS that might guide further treatment decisions. [Table: see text]

What is the Optimal Treatment Strategy after Sarcoma R2 Surgery?

Soft tissue sarcomas (STS) are rare tumours of mesenchymal origin, most commonly occurring in the extremity but also in the retroperitoneum. The curative treatment for STS is radical surgery with wide margins, in some cases in combination with perioperative radiotherapy and chemotherapy. Nonradical resection (R2) of STS has been an emerging issue in recent decades, as optimal subsequent management remains debatable. Similarly, there is still no consensus on optimal surgical margins. Combining multiple treatment modalities in adjuvant therapy can achieve local and distant control in patients following surgery with positive margins. Patients who have undergone nonradical resection therefore require additional surgical interventions, and adjuvant radiotherapy resulting in a better prognosis but a higher number of complications. Following non-radical treatment, patients with limb and trunk wall sarcomas and retroperitoneal sarcomas should also undergo increased oncological surveillance. Given the potential issues that may emerge in such clinical situations, it is crucial to up-date the current guidelines to enhance the long-term prognosis of these patients.

HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study

HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.

A Two-Step Approach to the Surgical Treatment of Soft-Tissue Sarcomas.

Background: Nowadays, limb-sparing procedures are the gold standard in the treatment of soft-tissue sarcomas of the limbs. Wide tumor resection with appropriate oncological margins, reconstruction, and stabilization of the involved bone and joint and restoration of the soft tissue lost are essential in order to obtain good clinical and functional outcomes. Tumor excision and soft-tissue reconstruction performed in one-step surgery is chosen by many centers as the preferred approach; however, according to our experience in some selected patients, two-step surgery performed using a dermal regeneration template first and then a margin revision, taking into account the definitive results of the anatomopathological exam conducted over the surgical specimen from the previous surgery, associated with definitive reconstruction surgery over a healthy bed of granulated tissue, showed many potential benefits. Methods: A retrospective observational study was conducted on thirteen patients who underwent a two-step reconstruction procedure using dermal substitution after soft-tissue sarcoma excision. Results: Clinically, the enrolled patients achieved excellent contour and cosmesis of their surgical wounds, with a mean VSS value of 3.07. During the follow-up period, no local recurrences were observed in any patient. Conclusions: Two-step surgery represents the most suitable solution to allow surgical radicality with minimal recurrency and adequate soft-tissue reconstruction, avoiding the possibility of wasting autologous tissue. Our patients generally embraced this approach and the management that followed.

Predicting Trabectedin Efficacy in Soft Tissue Sarcoma: Inflammatory Biomarker Analysis.

Trabectedin is used as a treatment for advanced-stage soft tissue sarcomas (STSs), particularly liposarcoma and leiomyosarcoma. Aside from its direct effect on tumor cells, trabectedin can affect the immune system in the tumor microenvironment. This study aimed to evaluate whether inflammatory biomarkers predict trabectedin efficacy in STSs. We retrospectively reviewed the clinical features and outcomes of patients with STS treated with trabectedin at our institution between 2016 and 2020. The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI=neutrophil × monocyte/lymphocyte) were calculated based on the blood samples obtained prior to trabectedin treatment initiation. Analyses of overall survival (OS) and progression-free survival (PFS) were performed according to various factors. Of the 101 patients identified, 54 had L-sarcoma (leiomyosarcoma: 30; liposarcoma: 24), and 47 had other types of STSs. Elevated SIRI, NLR, PLR, LMR, and C-reactive protein (CRP) were associated with worse PFS (p<0.001, p=0.008, p=0.027, p=0.013, and p<0.001, respectively) according to the results of the univariate analysis. Multivariate analysis showed that elevated SIRI, other histology, and CRP were associated with poor PFS (p=0.007, p=0.008, and p=0.029, respectively). In addition, the multivariate analysis of OS showed that SIRI was an independent prognostic factor (hazard ratio=2.16, p=0.006). Pretreatment SIRI can be considered a biomarker for the prognostic prediction of patients with STS treated with trabectedin.

Impact of resection margin on outcome in soft-tissue sarcomas of the extremities treated with limb-sparing surgery and postoperative radiotherapy

BackgroundThe standard curative treatments for extremity soft tissue sarcoma (ESTS) include surgical resection with negative margins and perioperative radiotherapy. However, the optimal resection margin remains controversial. This study aimed to evaluate the outcomes in ESTS between microscopically positive margin (R1) and microscopically negative margin (R0) according to the Union for International Cancer Control (UICC) (R + 1 mm) classification.MethodsMedical records of patients with localized ESTS who underwent primary limb-sparing surgery and postoperative radiotherapy between 2004 and 2015 were retrospectively reviewed. Patients were followed for at least 5 years or till local or distant recurrence was diagnosed during follow-up. Outcomes were local and distal recurrences and survival.ResultsA total of 52 patients were included in this study, in which 17 underwent R0 resection and 35 underwent R1 resection. No significant differences were observed in rates of local recurrence (11.4% vs. 35.3%, p = 0.062) or distant recurrence (40.0% vs. 41.18%, p = 0.935) between R0 and R1 groups. Multivariate analysis showed that distant recurrences was associated with a Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade (Grade III vs. I, adjusted hazard ratio (aHR): 12.53, 95% confidence interval (CI): 2.67–58.88, p = 0.001) and tumor location (lower vs. upper extremity, aHR: 0.23, 95% CI: 0.07–0.7, p = 0.01). Kaplan–Meier plots showed no significant differences in local (p = 0.444) or distant recurrent-free survival (p = 0.161) between R0 and R1 groups.ConclusionsR1 margins, when complemented by radiotherapy, did not significantly alter outcomes of ESTS as R0 margins. Further studies with more histopathological types and larger cohorts are necessary to highlight the path forward.

Alterations in Plasma Lipid Profile before and after Surgical Removal of Soft Tissue Sarcoma.

Soft tissue sarcoma (STS) is a relatively rare malignancy, accounting for about 1% of all adult cancers. It is known to have more than 70 subtypes. Its rarity, coupled with its various subtypes, makes early diagnosis challenging. The current standard treatment for STS is surgical removal. To identify the prognosis and pathophysiology of STS, we conducted untargeted metabolic profiling on pre-operative and post-operative plasma samples from 24 STS patients who underwent surgical tumor removal. Profiling was conducted using ultra-high-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry. Thirty-nine putative metabolites, including phospholipids and acyl-carnitines were identified, indicating changes in lipid metabolism. Phospholipids exhibited an increase in the post-operative samples, while acyl-carnitines showed a decrease. Notably, the levels of pre-operative lysophosphatidylcholine (LPC) O-18:0 and LPC O-16:2 were significantly lower in patients who experienced recurrence after surgery compared to those who did not. Metabolic profiling may identify aggressive tumors that are susceptible to lipid synthase inhibitors. We believe that these findings could contribute to the elucidation of the pathophysiology of STS and the development of further metabolic studies in this rare malignancy.

First-Line Anlotinib Treatment for Soft Tissue Sarcoma in Chemotherapy-Ineligible Patients: An Open-label, Single-arm, Phase 2 Clinical Trial.

Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma (LA/M STS) is chemotherapy based on anthracyclines, but patient tolerance of chemotherapy is limited. The present trial (NCT03792542) investigated the use of anlotinib as first-line treatment for patients with advanced STS, in particular liposarcoma (LPS). Eligible patients were previously untreated, pathologically confirmed, unresectable LA/M STS cases. Anlotinib was given orally at a dose of 12 mg once daily from day 1 to day 14 every 3 weeks until disease progression or intolerable adverse events (AEs) occurred. The primary endpoint was progression-free survival (PFS) and the secondary endpoints overall survival (OS), the objective response rate and the disease control rate (DCR). The safety profile was also evaluated. Forty patients were enrolled from April 2019 to Jun 2022 and are included in the intention-to-treat analysis. The median PFS was 6.83 months [95% confidence interval (CI): 4.17-8.71] and the median OS 27.40 months (95% CI: 16.43-not evaluable); 1 patient reached partial response and 26 attained stable disease, with a DCR of 67.5% (27/40). Median PFS and OS times for LPS patients were 8.71 and 16.23 months, respectively. Ten (25.0%) patients had treatment-related AEs ≥ grade 3, with in particular a higher incidence of hypertension (15.0%) and proteinuria (7.5%). The findings suggest a potential benefit in employing front-line anlotinib to treat patients with STS, who are not eligible for cytotoxic chemotherapy. Of note, the clinical outcomes for the LPS subgroup of patients were encouraging.

Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2

Soft-tissue sarcomas (STS) emerges as formidable challenges in clinics due to the complex genetic heterogeneity, high rates of local recurrence and metastasis. Exploring specific targets and biomarkers would benefit the prognosis and treatment of STS. Here, we identified RCC1, a guanine-nucleotide exchange factor for Ran, as an oncogene and a potential intervention target in STS. Bioinformatics analysis indicated that RCC1 is highly expressed and correlated with poor prognosis in STS. Functional studies showed that RCC1 knockdown significantly inhibited the cell cycle transition, proliferation and migration of STS cells in vitro, and the growth of STS xenografts in mice. Mechanistically, we identified Skp2 as a downstream target of RCC1 in STS. Loss of RCC1 substantially diminished Skp2 abundance by compromising its protein stability, resulting in the upregulation of p27Kip1 and G1/S transition arrest. Specifically, RCC1 might facilitate the nucleo-cytoplasmic trafficking of Skp2 via direct interaction. As a result, the cytoplasmic retention of Skp2 would further protect it from ubiquitination and degradation. Notably, recovery of Skp2 expression largely reversed the phenotypes induced by RCC1 knockdown in STS cells. Collectively, this study unveils a novel RCC1-Skp2-p27Kip1 axis in STS oncogenesis, which holds promise for improving prognosis and treatment of this formidable malignancy.

Pazopanib attenuated bleomycin-induced pulmonary fibrosis via suppressing TGF-β1 signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with a high mortality rate and limited treatment efficacy. Nintedanib, a tyrosine kinase inhibitor, is clinically used to treat pulmonary fibrosis. At present, only nintedanib is on the market for the treatment of pulmonary fibrosis. Pazopanib is a drug for the treatment of renal cell carcinoma and advanced soft tissue sarcoma. In this study, we explored whether pazopanib can attenuate bleomycin (BLM)-induced pulmonary fibrosis and explored its antifibrotic mechanism. In vivo and in vitro investigations were carried out to investigate the efficacy and mechanism of action of pazopanib in pulmonary fibrosis. In vivo experiments showed that pazopanib can alleviate pulmonary fibrosis caused by BLM, reduce the degree of collagen deposition and improve lung function. In vitro experiments showed that pazopanib suppressed transforming growth factor-β1 (TGF-β1)-induced myofibroblast activation and promoted apoptosis and autophagy in myofibroblasts. Further mechanistic studies demonstrated that pazopanib inhibited the TGF-β1/Smad and non-Smad signaling pathways during fibroblast activation. In conclusion, pazopanib attenuated BLM-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway. Pazopanib inhibits myofibroblast activation, migration, autophagy, apoptosis, and extracellular matrix (ECM) buildup by downregulating the TGF-β1/Smad signal route and the TGF-β1/non-Smad signal pathway. It has the same target as nintedanib and is a tyrosine kinase inhibitor.

Abstract 6456: The utility of clinical sequencing in the diagnosis and treatment of soft tissue sarcomas; Real world data based on nation-wide database

Abstract Purpose: Soft tissue sarcomas (STS) are rare and heterogeneous tumors arising from mesenchymal connective tissue, accounting for approximately 1%-2% of all malignancies. Due to their rarity and heterogeneity, it is challenging for accurate diagnosis, prognosis, and treatment of sarcoma. Recently, next-generation sequencing (NGS)-based comprehensive cancer genome profiling (CGP) has increasingly become a routine practice for patients with solid cancers worldwide. To collect genomic information and clinical characteristics of patients who underwent CGP, the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) has also been established since 2018 in Japan. Almost all the clinical and genomic data of patients who received CGP tests the had been collected in C-CAT. Here, we examined the utility of CGP test in the diagnosis and treatment of STS using this nation-wide database. Patients and Methods: We retrospectively evaluated the records of patients with STS who received F1CDx between 2019 and 2022 and registered in C-CAT. This assay carries 324 genes and determines nucleotide substitutions, insertions/deletions, and copy number (CN) alterations of 309 genes, fusions of 36 genes, tumor mutation burden (TMB) and microsatellite instability (MSI). High TMB (TMB-H) was defined as a TMB value &amp;gt;10 muts/Mb. Ranges of the MSI score were assigned MSI-High (MSI-H) or microsatellite stable (MSS). Results: From 2019 to 2022, 1387 patients with STS were registered in C-CAT. The histological types included leiomyosarcoma in 357 patients, dedifferentiated liposarcoma in 178 patients, and undifferentiated pleomorphic sarcoma in 82 patients, and the others. The most commonly altered genes included TP53, CDKN2A, Rb1, and CDKN2B. Among the 1387 cases, we observed 110 fusion events in 108 cases (7.7%), and 2 cases showed 2 types of fusion transcripts. Fifteen (2.8%) patients were re-classified based on the detection of highly histology-specific translocations. Among them, an initial diagnosis of sarcoma NOS was classified as Ewing Sarcoma (EWSR1-FLI1 in 2 patients), NTRK-rearranged spindle cell neoplasm (NTRK fusion in 3 patients), CIC-rearranged sarcoma (CIC-DUX4 in 3 patients), and sarcoma with BCOR genetic alterations (BCOR-ZC3H7B in 1 patient) as these gene fusions were identified. Druggable gene alterations was detected in 347 patients (25%) and 55 patients (4%) who received genotype-matched therapy. In 38 patients for whom the effect of treatment could be evaluated, complete response and partial response were achieved in 2 (5%) and 10 (26%) patients, respectively. Discussion: In conclusion, the comprehensive genomic profiling test appears to be an important tool in the diagnosis and treatment of sarcomas. Citation Format: Eiji Nakada, Tomohiro Fujiwara, Toshi Kunisada, Shota Takihira, Daisuke Ennishi, Hideki Yamamoto, Kiichiro Ninomiya, Shuta Tomida, Mashu Futagawa, Akira Hirasawa, Shinichi Toyooka, Toshifumi Ozaki. The utility of clinical sequencing in the diagnosis and treatment of soft tissue sarcomas; Real world data based on nation-wide database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6456.

Abstract 6566: Clinical evaluation of functional combinatorial precision medicine platform to predict treatment outcomes and enhance combination therapy design in soft tissue sarcomas

Abstract Purpose: Soft tissue sarcomas (STS) are a collection of heterogenous cancers with limited range of treatment options and poor outcomes. First line treatment for most STS is anthracycline-based, with gemcitabine-based combinations, pazopanib or ifosfamide as treatment options in refractory/relapsed STS. There is a clinical unmet need to improve treatment options for STS as median time to progression following second- and third-line treatments is less than 4 months. We have previously demonstrated in a 71-patient relapsed/refractory non-Hodgkin’s lymphoma clinical study that a functional precision medicine platform can effectively guide treatment, with several exceptional responders (Science Translational Medicine, 2022). This ex vivo drug sensitivity platform, quadratic phenotypic optimization platform (QPOP), analyses a predesigned array of 155 test combinations performed on a primary patient sample to rank and compare all possible therapeutic combinations from a 12-drug set. In this study, we evaluated clinical concordance of QPOP to predict treatment outcomes in an STS cohort. We also explored QPOP’s combination therapy ranking function to identify novel combinations that may benefit larger groups of STS patients when appropriately guided. Experimental Detail: A 12-drug set comprised of STS standard of care, FDA approved drugs and promising investigational drugs was evaluated in QPOP analysis of primary STS tumor samples. Ex vivo cultures of primary STS samples were treated with a predesigned array of 155 test combinations to provide a quantitative phenotypic output for each test combination. This dataset was analyzed by QPOP to rank all possible drug combinations towards a predicted treatment outcome. Concordance analysis was then performed comparing patient sample results with either parallel treatment initiated at time of sample collection or physician choice to use QPOP-guided treatment. Validation of QPOP-derived top-ranked drug combinations was also performed. Results: 12-drug, 3-level QPOP was successfully performed on 45 of 51 primary patient samples. Clinical concordance analysis showed QPOP had a total predictive value (TPV) of 76.9% and an AUCROC of 85.7%. Exceptional responders to guided treatment with pazopanib or eribulin were observed. Additionally, top-ranked epigenetic-based combinations were identified as effective across multiple STS subtypes and validated preclinically. Conclusion: The results show the potential for QPOP to predict clinical response in solid cancers, such as STS. Furthermore, QPOP can improve drug development pipelines through patient samples-based design of effective combinations with investigational drugs or underutilized drugs that may benefit larger populations of patients or specific subgroups of patients. Citation Format: Edward Kai-Hua Chow, Sharon P. Chan, Tan Boon Toh, Masturah Rashid, Valerie S. Yang. Clinical evaluation of functional combinatorial precision medicine platform to predict treatment outcomes and enhance combination therapy design in soft tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6566.

Abstract 4844: Epidemiology of bone and soft-tissue sarcomas: A two-decade analysis of the surveillance, epidemiology, and end results program

Abstract In the United States, ~15000 cases of bone and soft-tissue sarcomas are diagnosed annually, representing roughly 1% of all incident cancers. While several studies have analyzed independent predictors of outcomes for these sarcomas, small samples and confounding bias have limited their ability to establish reliable conclusions. The present analysis provides a comprehensive epidemiological description of patients with any of 16 distinct bone and soft-tissue sarcomas by querying the Surveillance, Epidemiology, and End Results database between 2000 and 2020. Incidence, prevalence, incidence-based mortality, survival rates, and case-fatality ratios were computed. Using patient age, sex, race, and ethnicity, as well as tumor size, grade, and stage as covariates, multivariable survival Cox proportional hazards regression analyses were performed to model hazard ratios (HRs) and identify independent predictors of worse prognosis. Only patients with myosarcoma and fibrous histiocytoma witnessed a decrease in the prevalence of their disease over time (both, p&amp;lt;0.05). The incidence of chondrosarcoma and synovial sarcoma increased in White and Asian patients but decreased in Black individuals (both, p&amp;lt;0.001), while their case-fatality rates remained constant and increased, respectively, regardless of race and ethnicity (all, p&amp;lt;0.05). Case-fatality rates only declined significantly for White and Non-Hispanic patients with solitary fibrous tumor (both, p&amp;lt;0.05). Aside from alveolar soft-part sarcoma and clear cell sarcoma, a 10-year increase in age of patients with bone and soft-tissue sarcomas resulted in 18% to 61% higher likelihood of death (all, p&amp;lt;0.05). For most malignancies, having a tumor size greater than 5 cm yielded a 37% to 189% higher likelihood of death. While incidence trends suggest improvements in diagnostic techniques and early tumor detection, survival and case-fatality trends indicate potential for advancement in treatment for most bone and soft-tissue sarcomas. Citation Format: Marc El Beaino, Rachel Baum, Katherine M. Connors, Karim Masrouha, Santiago A. Lozano-Calderon, Patrick P. Lin. Epidemiology of bone and soft-tissue sarcomas: A two-decade analysis of the surveillance, epidemiology, and end results program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4844.