Purpose of Review
Desmoid fibromatosis (DF) is a locally aggressive clonal neoplasm with locally aggressive behavior and no metastatic potential. Historical treatment of DF has consisted primarily of ...up-front surgery when feasible. In recent years, recognition that DF can spontaneously stabilize or involute has allowed for many patients to be managed with watchful waiting rather than intervention. This review is intended to review recent developments in the treatment of DF.
Recent Findings
Recent studies have demonstrated prospectively that patients with DF often have improvement in their lesions without intervention, enabling an initial period of surveillance as a standard option for patients with mild symptoms. Given the lengthening list of effective systemic treatments, including sorafenib, pazopanib, and experimental agents, there has been a less reliance on local therapies for those patients who require treatment.
Summary
For patients with DF that require treatment, there is a growing list of options that includes radiation therapy (RT), percutaneous ablation, and a growing list of systemic agents with favorable toxicity profiles.
Purpose
Metastatic phyllodes tumors of the breast (MPT) are rare breast neoplasms, limiting development of standardized treatment approaches. We sought to characterize the largest group of MPT thus ...far reported, evaluating systemic therapy outcomes.
Methods
Adult patients diagnosed with MPT between 1993 and 2015 and followed at MD Anderson Cancer Center were selected for retrospective chart review. Systemic therapy was sorted into: adriamycin/ifosfamide (AI), other anthracycline regimens, other ifosfamide regimens, gemcitabine-based regimens, and other. Given one patient may have received more than one regimen, we assumed that the effects of each regimen were independent from previous therapy. Median overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method. Log-rank test was performed to evaluate the difference in OS between patient characteristics groups, and the differences in PFS between the five chemotherapy regimens.
Results
We identified 50 MPT patients, with 31 patients receiving 61 systemic regimens. Median OS was 10.7 months (95% CI: 8.67, 16.5). AI had a PFS of 9.10 months (95% CI: 5.03, 14.2), other ifosfamide regimens had a PFS of 5.10 months (95% CI: 0.67, 12.1), other anthracycline regimens had a PFS of 3.65 months (95% CI: 1.17, 7.90), gemcitabine-based regimens had a PFS of 2.80 months (95% CI: 1.83, 4.60), and other regimens had a PFS of 1.67 months (95% CI: 1.13, 7.77).
Conclusion
MPT patients are a unique population with limited characterization to date. Our study demonstrates activity of multiple sarcoma-directed chemotherapy regimens, with ifosfamide-containing regimens having the longest PFS.
Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen ...receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have direct clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.
Introduction
Undifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective ...in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes.
Material and methods
Surgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters.
Results
Samples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (
p
=0.009). CD39 expression was significantly correlated with PD1 expression (primary:
p
=0.002, recurrent:
p
=0.004, metastatic:
p
=0.001), PD-L1 expression (primary:
p
=0.009), and CD3+ cell densities (primary:
p
=0.016, recurrent:
p
=0.043, metastatic:
p
=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (
p=
0.015), and both were also correlated with CD163+ cell densities (CD39
p=
0.013; CD73
p<
0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio HR=0.33;
p
=0.010) were independently associated with OS (CD3+, HR=0.19,
p
<0.001; CD8+, HR= 0.33,
p
=0.010) and DFS (CD3+, HR=0.34,
p
=0.018; CD8+, HR=0.34,
p
= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank
p
<0.0001) and DFS (
p
<0.001).
Conclusion
We identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS.
The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in
,
, or components of the succinate dehydrogenase (SDH) complex (
,
,
, and
genes). A small fraction ...of GISTs lack alterations in
,
, and
. We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs.
We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients.
Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5-191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a
V600E mutation and two with
loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with
LOF mutations, one with
fusion (
), one with
deletion, one with
gain-of-function (GOF) mutation (K654E), one with
LOF mutation (T367fs*), one with Aurora kinase A fusion (
), and one with
deletion. Patients had better responses with molecularly targeted therapies than with imatinib.
Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to
/
-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.
Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other ...high-grade pleomorphic STS patients are available.
The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution.
This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in trials for which results are not yet published were excluded.
Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included. The median age was 52 years. A total of 26 patients (72%) had UPSs and 10 patients (28%) had other high-grade pleomorphic sarcomas. The median follow-up time was 8.8 months. The median PFS was 2.9 months. The 3-month PFS and 6-month PFS were 46% and 32%, respectively. The median OS was 12.9 months. The 12-month OS and 24-month OS were 53% and 29%, respectively. The best response, previous RT, and type of ICB treatment were significantly and independently associated with shorter PFS (
= 0.0012,
= 0.0019 and
= 0.036, respectively). No new safety signal was identified, and the toxicity was overall manageable with no toxic deaths and only four patients (11%) stopping treatment due to toxicity.
Real-world retrospective data are consistent with the published literature, with a promising 6-month PFS of 32%. Partial or stable responders to ICB treatment have significantly improved PFS compared to progressors.
Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit ...from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000-2021 were included. Patients were grouped by drug sequence: ripretinib-avapritinib (RA) or avapritinib-ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan-Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2-5.95) for RA and 4.73 months (1.87-15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86-18.99) for AR and 4.11 months (1.91-11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8-50.53) and 33.7 (20.03-50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing.
Background: Rhabdomyosarcomas are the most common soft tissue sarcoma in children, and pediatric alveolar rhabdomyosarcoma (ARMS) prognosis has improved based on cooperative studies. However, in ...adults, ARMS is significantly rarer, has poorer outcomes, and currently lacks optimal treatment strategies. Objective: This study aimed to evaluate the clinical outcome of an adult ARMS population with different front-line systemic chemotherapies and determine if any chemotherapy regimen is associated with improved survival. Materials and methods: This is a retrospective study of histologically confirmed fusion-positive ARMS patients over 18 years of age, who were treated at MD Anderson Cancer Center (MDACC) from 2004 to 2021 and received systemic chemotherapy. Descriptive clinical statistics were performed, including staging, front-line chemotherapy, multimodal therapy usage, response rates, and survival analyses. Results: 49 ARMS patients who received upfront chemotherapy were identified. Locoregional treatments included radiotherapy (RT) alone (29%, n = 14), surgery alone (10%, n = 5), or both (45%, n = 22). Median overall survival (OS) for the entire cohort was 3.6 years, and the overall response rate to systemic therapy was 89%. No chemotherapy regimen showed OS benefit, specifically analyzing the pediatric-based vincristine, actinomycin-D, cyclophosphamide (VAC) or adult-based vincristine, doxorubicin, ifosfamide (VDI) regimens, even when controlled for other clinical risk factors. Conclusion: In this single-center contemporary series, adult ARMS patient outcomes remain poor. There was no statistically significant OS difference in patients who did or did not receive adult or pediatric based ARMS regimens, although a high overall response rate to chemotherapy was seen across the entire cohort. Based on these observations, further randomized prospective studies are necessary to delineate which frontline chemotherapy regimen is most beneficial in this rare adult cancer.
Limited information exists on the clinical behavior of the Ewing sarcoma family of tumors (ESFT) of the kidney. We reviewed the records of 30 patients (aged 8-69 years) with ESFT of the kidney seen ...at our institution between 1990 and 2013. We analyzed the event-free survival (EFS) and overall survival (OS) for associations with patient demographics, disease group, tumor size, tumor thrombus, and treatment. Six patients (20%) had tumors confined to the kidney (Group I), seven (23.3%) had local tumor extension beyond the kidney (Group II), and 17 (56.7%) had distant metastasis at diagnosis (Group III). Twenty-five (83.3%) patients underwent radical (19 upfront, five delayed) or partial (one upfront) nephrectomy, 25 (83.3%) chemotherapy and four (13.3%) radiotherapy. The 4-year EFS and OS were 43% (95% CI, 26-61%) and 63% (95% CI, 46-81%), respectively. EFS and OS were significantly associated with disease group and chemotherapy (
< 0.039). The presence of tumor thrombus in renal vein and/or inferior vena cava was associated with worse EFS (
= 0.053). Patients with disease confined to the kidney treated with nephrectomy and adjuvant chemotherapy have favorable outcomes. Local tumor extension beyond the kidney, tumor thrombus, and distant metastasis are unfavorable factors that warrant intensification or novel approaches of therapy.
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