Clinical Cancer Research最新文献

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

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

Results: The overall ORR in the cohort was 16.7%. The histologic subtypes with the highest ORR were Kaposi sarcoma (KS, 66.7%), alveolar soft part sarcoma (ASPS, 50%), angiosarcoma (33.3%), myxofibrosarcoma (MFS, 28.6%), and undifferentiated pleomorphic sarcoma (UPS, 27.8%). The subtypes with the lowest ORR were osteosarcoma (0%), synovial sarcoma (0%), and liposarcoma (3.7%). The subtypes with the highest median PFS were KS (median not reached), ASPS (median not reached), MFS (27.4 months), and UPS (11.3 months). The ORR for sarcomas with PD-L1 ≥ 1% was 27.8% (P = 0.02), whereas the ORR for sarcomas with tumor mutational burden ≥10 mutations per megabase of DNA was 28.6% (P = 0.20).

Conclusions: ORR and PFS were highly variable across sarcoma histologic subtypes. In this large analysis, KS, ASPS, angiosarcoma, MFS, and UPS demonstrated the highest ORR and longest PFS while osteosarcoma, synovial sarcoma, and liposarcoma had the lowest ORR and shortest PFS. PD-L1 expression was also associated with increased ORR. Our findings provide further insight into understanding the sarcoma histologic and immunologic factors that correspond with response to ICI.

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) has limited treatment options and a poor prognosis. Recently, PSMA-targeted alpha particle therapy agents using Actinium-225 (225Ac) have shown promising results for prostate cancer treatment, but a significant fraction of patients with advanced mCRPC demonstrate loss of PSMA expression. We have previously reported that PSMA-null and PSMA-positive tumors can be detected and treated effectively with CD46-targeted radiopharmaceuticals. This study evaluates the CD46-targeting PET imaging agent [89Zr]DFO-YS5 and the radioimmunotherapy agent [225Ac]Macropa-PEG4-YS5 in disseminated prostate cancer tumors.

Experimental design: Microtumor lesions, primarily observed in the liver, kidneys, and lungs, were successfully detected with [89Zr]DFO-YS5 PET imaging. We used disseminated 22Rv1 tumors for biodistribution studies, dosimetry assessments, and therapeutic efficacy evaluations of [225Ac]Macropa-PEG4-YS5.

Results: Quantitative digital alpha-particle autoradiography revealed high radiation dose deposition from [225Ac]Macropa-PEG4-YS5 in microtumors compared to surrounding liver tissues, although in larger lesions (>1 mm diameter) the dose distribution was heterogeneous. Early treatment of smaller disseminated tumors with uniform radiation dose was more effective in ablating tumors and promoting survival. In late-stage lesions of large size, heterogeneous dose deposition limited therapeutic efficacy, requiring higher administered activity to achieve a complete response.

Conclusions: Our findings highlight that [225Ac]Macropa-PEG4-YS5 holds the potential for clinical translation for metastatic prostate cancer and reinforces the value of microdosimetry in understanding the efficacy of and resistance to targeted alpha therapy.

Purpose: To evaluate whole-tumor histogram analysis of diffusion kurtosis imaging (DKI), intravoxel incoherent motion (IVIM), and dynamic contrast-enhanced MRI (DCE-MRI), in predicting the efficacy of imatinib, a c-KIT inhibitor, for treating patient derived models derived from sinonasal mucosal melanomas (MMs).

Experimental design: This study included 38 patients with histologically confirmed sinonasal MM, who underwent DKI, IVIM, and DCE-MRI. Patient-derived tumor xenograft (PDX) models and precision-cut tumor slices (PCTS) were established to evaluate tumor response to imatinib. Whole-tumor histogram analysis was conducted on imaging parameters, and logistic regression models were applied to determine the predictive value of these metrics in differentiating responders from non-responders.

Results: Among the 38 sinonasal MM patients, 12 were classified as responders and 26 as non-responders based on PDX and PCTS model responses to imatinib. The DKI model revealed significant differences in mean, median, P10, and P90 values of Dk and K between responders and non-responders (P < 0.05). The IVIM model indicated significant differences in P10 and mean values of D, with kurtosis f being a strong predictor. The DCE-MRI model, using the P90 Ktrans metric, demonstrated robust predictive performance, achieving an AUC of 0.89, with 80.77% specificity and 91.67% sensitivity. The combined logistic model integrating DKI, IVIM, and DCE-MRI metrics produced the highest predictive accuracy, with an AUC of 0.90.

Conclusions: Whole-tumor histogram analysis of DKI, IVIM, and DCE-MRI offers a non-invasive method for predicting the efficacy of c-KIT inhibitors in sinonasal MMs, presenting valuable implications for guiding targeted treatment in this rare cancer type.

Purpose: PTEN hamartoma tumour syndrome (PHTS) is an autosomal dominant cancer-predisposition and overgrowth syndrome occurring due to pathogenic germline variants in the PTEN gene, with an increased risk of both benign and malignant tumours involving the breast, colon, endometrium, thyroid, skin, and kidney. The objective of these clinical guidelines was to use the latest knowledge to generate an international consensus resource for providers, researchers, and individuals with PHTS on the best practices in the surveillance and management of cancer and overgrowth in PHTS.

Experimental design: The International PHTS Cancer and Overgrowth Guidelines Working Group was established, comprising a core group of six international experts in the diagnosis and management of PHTS. The Working Group held joint meetings with PHTS individuals and their advocates. Informed by the literature, the Working Group met regularly between 2022 and 2024 to produce guideline statements, refined through iterative feedback. A modified Delphi approach was used with an independent external panel of PHTS, genetics and cancer experts to establish final consensus guidelines.

Results: Clinical consensus recommendations for the surveillance and management of cancer and overgrowth in individuals with PHTS were formed. Guidelines encompass the recommended practices in cases of breast, colon, endometrial, thyroid, and kidney cancers, as well as overgrowths.

Conclusions: The clinical management of individuals with PHTS is complex and necessitates a multidisciplinary approach. We generated international consensus guidelines for the surveillance and management of cancer and overgrowth in PHTS aiming at improving care for affected individuals and families.

Schwannomatoses (SWN) are distinct cancer predisposition syndromes caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas and less commonly ependymoma. SMARCB1-related SWN is a familial SWN-syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence of radiation. These individuals do not develop bilateral vestibular schwannomas. Finally, patients with LZTR1-related SWN typically present with peripheral schwannomas, and unilateral vestibular schwannomas have been reported. The following perspective is intended to highlight the clinical presentation and international tumor surveillance recommendations across these SWN-syndromes.

Purpose: AZD8701 uses next-generation antisense oligonucleotide (ASO) technology to selectively reduce human forkhead box P3 (FOXP3) expression in regulatory T cells, reversing their immunosuppressive function. FOXP3 ASOs alone or with programmed cell death protein (ligand) 1 (PD-[L]1) inhibition attenuated tumor growth in mice. We report a phase I study of AZD8701 alone or combined with durvalumab in patients with advanced solid tumors.

Methods: Eligible patients had solid tumors and had received prior standard-of-care treatment including anti-PD-(L)1 therapy. Patient cohorts were treated with AZD8701 intravenously (IV) weekly at escalating doses, either alone (60-960 mg) or combined (240-720 mg) with durvalumab 1,500 mg IV every 4 weeks. The primary objective was safety and tolerability, with the aim of determining the maximum tolerated dose.

Results: Forty-five patients received AZD8701 monotherapy and 18 received AZD8701 with durvalumab. One dose-limiting toxicity (increased alanine aminotransferase [ALT]) occurred with AZD8701 960 mg. The most common adverse events (AEs) related to AZD8701 monotherapy were fatigue (22.2%), asthenia, pyrexia, and increased ALT (20%, each); the safety profile was similar when combined with durvalumab. With AZD8701 monotherapy, 24.4% and 15.6% of patients had stable disease for ≥16 and ≥24 weeks, respectively; one patient treated with AZD8701 720 mg and durvalumab had a partial response. FOXP3mRNA changes were heterogeneous (8/13 patients showed reduction), with no clear dose relationship. ASO accumulated in the tumor epithelium and stroma.

Conclusions: This study demonstrates the clinical feasibility of ASO therapy, with generally manageable AEs, FOXP3 knockdown, and ASO delivery to the tumor.

Purpose: Plasma-based liquid biopsy tests can detect tumor-specific genetic alterations and offer many advantages that complement tissue-based Comprehensive Genomic Profiling (CGP). However, age-related clonal hematopoiesis (CH) mutations can confound liquid biopsy results and potentially lead to incorrect therapy choice.

Experimental design: We assessed the landscape of 16,812 liquid profiles across 49 cancer types using the Caris Assure assay, a whole exome and whole transcriptome NGS workflow that independently sequences both plasma-derived cell-free total nucleic acids (cfTNA) as well as the white blood cell DNA and RNA from the buffy coat. The variant source was identified algorithmically by comparing plasma and buffy coat variant frequency and read quality metrics.

Results: 42.3% of 16,812 patients presented at least one CH variant among reportable clinical genes. We found 39% of BRCA2 variants to be of CH origin, as well as 37.9% of CHEK2, 27.4% of BRCA1, 20.1% of ATM, 7.3% NRAS, 5.8% BRAF, 2.1% EGFR, 2.1% KRAS, and 18.5% TP53. For patients aged 65-69, the median proportion of CH variant classification was 20%, whereas it was 33% for patients aged 70-74, 33% for ages 75-79, and 50% for ages 80+. We found high rates of CH detected in what would be otherwise druggable targets in many cancer types typically treated with PARP inhibitors, including breast, female genital tract, ovarian, pancreatic, prostate, and endometrial cancers.

Conclusion: This large study highlights the need for thorough CH classification during liquid biopsy to appropriately recommend therapies, especially PARP inhibitors.

Defining patterns of acquired resistance has important prognostic and therapeutic implications in patients with lung cancer. Longitudinal biomarker analysis has enhanced our understanding of tumor biology and treatment response. However, the role of temporally informed biomarkers in guiding clinical decisions, such as local therapy intervention, remains unproven.