Histologic and immunologic factors associated with response to immune checkpoint inhibitors in advanced sarcoma.

Purpose: To characterize factors associated with response to immune checkpoint inhibitors (ICIs) in advanced sarcoma.

Experimental Design: This is a retrospective study with a cohort of 216 patients with advanced sarcoma treated with ICIs between 2016-2023 at Stanford Health Care. Overall survival (OS), progression free survival (PFS), objective response rates per RECIST criteria (ORR), and reason for ICI discontinuation were analyzed across histologic subtypes, ICI regimens, tumor mutational burden (TMB), and PD-L1 expression.

Recent advances in sarcoma therapy: new agents, strategies and predictive biomarkers.

Soft tissue and bone sarcomas are a heterogenous group of uncommon mesenchymal tumors with high unmet needs for novel therapeutic and diagnostic strategies. Despite many challenges that persist, innovative therapeutics are emerging. Here we provide a review of the studies presented at the 2024 American Society of Clinical Oncology annual meeting that were focused on sarcoma.

PTEN pathogenic variants are associated with poor prognosis in patients with advanced soft tissue sarcoma.

Background: We aimed to examine whether PTEN pathogenic variants (mutPTEN) were associated with overall survival (OS) in patients with advanced soft tissue sarcoma (STS) with the presence of one or more of the most common genomic alterations including p53, CDKN2A, RB1, and ATRX pathogenic variants.

Methods: This study included patients from Kaiser Permanente Northern California and Stanford Cancer Center with grade 2 or higher locally advanced and metastatic STS.

Results: A total of 174 patients had leiomyosarcoma (LMS), 136 had undifferentiated pleomorphic sarcoma (UPS), 78 had Liposarcoma (LPS), and 214 had other histology subtypes (Others).

Sex-dependent Prognosis of Patients with Advanced Soft Tissue Sarcoma.

Purpose: To examine whether overall survival (OS) differs for male and female patients with advanced soft-tissue sarcoma (STS).

Experimental Design: The study included patients from Kaiser Permanente Northern California and Stanford Cancer Center with grade 2 and 3 locally advanced or metastatic STS whose tumor underwent next-generation sequencing. We used Cox regression modeling to examine association of sex and OS adjusting for other important factors.

High-dimensional single-cell analysis unveils distinct immune signatures of peripheral blood in patients with pancreatic ductal adenocarcinoma.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with poor response to immune checkpoint inhibitors. The mechanism of such poor response is not completely understood.

Methods: We assessed T-cell receptor (TCR) repertoire and RNA expression at the single-cell level using high-dimensional sequencing of peripheral blood immune cells isolated from PDAC patients and from healthy human controls.

Sex- and Co-Mutation-Dependent Prognosis in Patients with SMARCA4-Mutated Malignancies.

Background: Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear.

Methods: This cohort included patients from Northern California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and , , , , and co-mutations.

Treatment of De-Differentiated Liposarcoma in the Era of Immunotherapy.

Well-differentiated/de-differentiated liposarcoma (WDLPS/DDLPS) is one of the most common histologic subtypes of soft tissue sarcoma (STS); however, treatment options remain limited. WDLPS and DDLPS both exhibit the characteristic amplification of chromosome region 12q13-15, which contains the genes and . DDLPS exhibits higher amplification ratios of these two and carries additional genomic lesions, including the amplification of chromosome region 1p32 and chromosome region 6q23, which may explain the more aggressive biology of DDLPS.

Gain-of-Function and Non-Gain-of-Function Mutations Are Associated With Differential Prognosis in Advanced Pancreatic Ductal Adenocarcinoma.

Purpose: To examine the impact of gain-of-function (GOF) and non-GOF mutations on prognosis of advanced pancreatic ductal adenocarcinoma (PDAC) among patients with , , and comutations.

Methods: This cohort included patients with locally advanced, recurrent, and de novo metastatic PDAC with next-generation sequencing performed from November 2017 to May 2022. We defined R175H, R248W, R248Q, R249S, R273H, R273L, and R282W as GOF and all other p53 mutations (mutp53) as non-GOF.

A Multicenter Virtual Multidisciplinary Sarcoma Case Conference Improves Outcome for a Rare Soft Tissue Sarcoma (Dermatofibrosarcoma Protuberans).

Introduction: The purpose of this study is to analyze the impact of a virtual multidisciplinary sarcoma case conference (VMSCC) on the outcomes of dermatofibrosarcoma protuberans (DFSP).

Methods: We compared margin status after surgery and disease-free survival (DFS) on two cohorts of patients with DFSP, one diagnosed from 2010 to 2015 and one from 2016 to 2020 (before and after virtual multidisciplinary sarcoma case conference (VMSCC) within Kaiser Permanente Northern California (KPNC), using Kaplan-Meier curves and Cox proportional hazard regression models.

Results: There was no significant difference between the two cohorts on demographics, tumor location, type of surgery, receipt of radiation, receipt of imatinib, or size of tumor.

Pain as Initial Presenting Symptom Is Associated With Delay to Seeking Medical Attention, Higher Risk of Relapse, and Shorter Survival in Patients With Early-Stage Extremity or Trunk Synovial Sarcoma.

BackgroundWhether the presenting symptom of pain vs mass impacts survival of early-stage synovial sarcoma is not known. Patients and MethodsThe authors investigated patients with early-stage extremity/trunk synovial sarcoma diagnosed from 2005 to 2017 at Kaiser Permanente Northern California for associations between the presenting symptom and survival. ResultsAmong 56 patients with early-stage extremity/trunk synovial sarcoma, median disease-free survival (DFS) was 20.

Gain-of-Function and Non-Gain-of-Function Mutations Are Differentially Associated With Sidedness-Dependent Prognosis in Metastatic Colorectal Cancer.

Purpose: To examine the association of gain-of-function (GOF) and non-gain-of-function (non-GOF) mutations with prognosis of metastatic right-sided (RCC) versus left-sided colorectal cancer (LCC).

Methods: This cohort study included patients with metastatic colorectal cancer (CRC) who had next-generation sequencing performed from November 2017 to January 2021. We defined R175H, R248W, R248Q, R249S, R273H, R273L, and R282W as GOF and all other mutp53 as non-GOF.

Rapid Response of a BRCA2/TP53/PTEN-Deleted Metastatic Uterine Leiomyosarcoma to Olaparib: A Case Report.

Patients with metastatic uterine leiomyosarcoma (uLMS) have poor prognosis due to limited treatment options, especially when disease progresses on doxorubicin and gemcitabine-docetaxel regimens. Here we report a patient whose metastatic uLMS contains a BRCA2 deep deletion as well as TP53 and PTEN deep deletion. The patient responded rapidly to olaparib, a poly (ADP-ribose) polymerase inhibitor, after progressing on gemcitabine-docetaxel, doxorubicin, and temozolomide regimens.

Fourteen-Day Gemcitabine-Docetaxel Chemotherapy Is Effective and Safer Compared to 21-Day Regimen in Patients with Advanced Soft Tissue and Bone Sarcoma.

Gemcitabine-docetaxel (G-D) combination is an effective chemotherapy for patients with advanced soft tissue and bone sarcoma, first developed with G administered on days 1 and 8, and D on day 8 every 21 days and later modified to be administered every 14 days in 2012. The 14-day regimen has become increasingly adopted. However, its efficacy and toxicities have not been compared.

Impact of a Virtual Multidisciplinary Sarcoma Case Conference on Treatment Plan and Survival in a Large Integrated Healthcare System.

Purpose: Quantifying the impact of a multidisciplinary cancer case conference on patient outcome and care quality remains challenging.

Patients And Methods: We prospectively investigated the impact of our virtual multidisciplinary sarcoma case conference (VMSCC) on treatment plan in patients presented to the VMSCC from July to October 2020 (prospective cohort) and retrospectively in patients with metastatic or locally advanced high-grade soft-tissue sarcoma (STS) reviewed in the VMSCC in 2016 and 2017 (high-grade STS cohort). We also investigated the factors related to the nonadherence to the VMSCC-recommended plan in both cohorts.

Complete Regression of Rhabdomyosarcoma in an Adult Secondary to Postoperative Wound Infection Following Limb Salvage Surgery: A Case Report.

Case Presentation: A 33-year old man presented with a 25-cm lower extremity embryonal rhabdomyosarcoma with presumed extensive nodal metastasis on positron emission topography scan. Neoadjuvant chemotherapy and radiation provided minimal response. Following limb salvage resection and flap coverage, a prolonged postoperative infection occurred requiring intravenous antibiotics and wound care over 5 months.

Durable Complete Remission of PD-L1 Positive NUT Carcinoma Treated With Concurrent Chemotherapy and Radiation.

Introduction: NUT carcinoma is an extremely rare disease and yet extremely aggressive with 2-year survival of only approximately 19% and median survival of 6 to 9 months.

Case Presentation: We report here 2 successfully treated patients with durable complete remission (CR) after concurrent chemotherapy and radiation using 2 completely different chemotherapy regimens. One patient had extremely high tumor burden and obtained CR with ifosfamide and etoposide concurrently with radiation.

Feasibility and Value of Establishing a Community-Based Virtual Multidisciplinary Sarcoma Case Conference.

Purpose: Management of soft tissue and bone sarcoma presents many challenges, both diagnostically and therapeutically, and requires multidisciplinary collaboration; however, such collaboration is often challenging to establish, especially in the community setting. We share our experiences of a virtual multidisciplinary sarcoma case conference (VMSCC).

Methods: We conducted retrospective review of the VMSCC data-initially via Webex, now Microsoft Teams-and the surveys of referring physicians to understand the feasibility and value of the VMSCC.

Single-cell RNA sequencing reveals compartmental remodeling of tumor-infiltrating immune cells induced by anti-CD47 targeting in pancreatic cancer.

Background: Human pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune checkpoint inhibitor (ICPi). While the mechanism is not completely clear, it has been recognized that tumor microenvironment (TME) plays key roles. We investigated if targeting CD47 with a monoclonal antibody could enhance the response of PDAC to ICPi by altering the TME.

Synergistic inhibition of pancreatic cancer with anti-PD-L1 and c-Myc inhibitor JQ1.

Human pancreatic ductal adenocarcinoma (PDAC) exhibits marginal responses to anti-PD-1/PD-L1 immunotherapy and its mechanism remains poorly understood. We have investigated the effect of anti-PD-L1 and c-Myc inhibition in PDAC. Using 87 patients with PDAC from our hospital database we found a significant correlation between the expression of PD-L1 and c-Myc.

Real-World Experiences with Pazopanib in Patients with Advanced Soft Tissue and Bone Sarcoma in Northern California.

Pazopanib was approved for advanced soft tissue sarcoma as a second- or third-line therapy based on the clinical trial "Pazopanib for metastatic soft-tissue sarcoma" (PALETTE). We hypothesized that the real-world experiences may be significantly different from the clinical trial results. We analyzed the response pattern of patients with advanced soft tissue and bone sarcoma who received pazopanib treatment between 1 January 2011 and 31 October 2018 in Kaiser Permanente Northern California.

Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib.

The mesenchymal-to-epithelial transition (MET) gene is altered and becomes a driver mutation in up to 5% of non-small-cell lung cancer (NSCLC). We report our institutional experience treating patients with MET exon 14 skipping (METex14) mutations, including responses to the MET inhibitors crizotinib and cabozantinib. We identified cases of NSCLC with METex14 mutations using an institutionally developed or commercial next-generation sequencing assay.

Mechanisms of Primary and Secondary Resistance to Immune Checkpoint Inhibitors in Cancer.

Immune checkpoint inhibitors (ICPis) have revolutionized cancer therapy with broad activities against a wide range of malignancies. However, in many malignancies their efficacy remains limited due to the primary resistance. Furthermore, a high percentage of patients develop progression due to the secondary resistance even after obtaining a response or achieving a stable disease.

WIPF1 antagonizes the tumor suppressive effect of miR-141/200c and is associated with poor survival in patients with PDAC.

Background: Aberrant expression of Wiskott-Aldrich syndrome protein interacting protein family member 1 (WIPF1) contributes to the invasion and metastasis of several malignancies. However, the role of WIPF1 in human pancreatic ductal adenocarcinoma (PDAC) remains poorly understood.

Methods: Human pancreatic cancer samples from PDAC patients were collected for methylation analysis.

Association of Inflammatory Markers with Disease Progression in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors.

Introduction: We investigated the effect of inflammatory biomarkers (neutrophil, platelet, and lymphocyte counts) on risk of progression in patients with metastatic melanoma treated with an immune checkpoint inhibitor targeting programmed cell death protein-1 (PD-1).

Methods: This retrospective cohort study included 108 patients with malignant melanoma treated with an anti-PD-1 checkpoint inhibitor from August 2014 through December 2015. The outcome was disease progression noted on imaging or clinical examination.