Clinical Cancer Research最新文献

Purpose: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses.

Experimental design: Clinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals.

Results: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 [23.8%; 95% confidence interval (CI), 19.7%, 28.5%] comparisons. In multivariable analysis, non-overall survival endpoints [OR, 2.16 (95% CI, 1.21, 3.87); P = 0.009] were associated with higher odds of PHVs, and immunotherapy comparisons [OR 1.94 (95% CI, 0.98, 3.86); P = 0.058] were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) prespecified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with restricted mean survival time or maximum combination test, of which 10 (71%) reported negative results.

Conclusions: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting nonproportional hazards to be misinterpreted.

Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous disease that carries the poorest prognosis of all breast cancers. Although novel TNBC therapies in development are frequently targeted toward tumors carrying a specific genomic, transcriptomic, or protein biomarker, it is poorly understood how these biomarkers are correlated.

Experimental design: To better understand the molecular features of TNBC and their correlation with one another, we performed multimodal profiling on a cohort of 95 TNBC. Our approach involved quantifying tumor-infiltrating lymphocytes through hematoxylin and eosin staining, assessing the abundance of retinoblastoma, androgen receptor, and PDL1 proteins through IHC, and carrying out transcriptomic profiling using the NanoString BC360 platform, targeted DNA sequencing on a subset of cases, as well as evaluating associations with overall survival.

Results: Levels of RB1 mRNA and RB proteins are better correlated with markers of retinoblastoma functionality than RB1 mutational status. Luminal androgen receptor tumors clustered into two groups with transcriptomes that cluster with either basal or mesenchymal tumors. Tumors classified as PDL1-positive by the presence of immune or tumor cells showed similar biological characteristics. HER2-low TNBC showed no distinct biological phenotype when compared with HER2-zero. The majority of TNBC were classified as basal or HER2-enriched by PAM50, the latter showing significantly improved overall survival.

Conclusions: Our study contributes new insights into biomarker utility for identifying suitable TNBC therapies and the intercorrelations between genomic, transcriptomic, protein, and cellular biomarkers. Additionally, our rich data resource can be used by other researchers to explore the interplay between DNA, RNA, and protein biomarkers in TNBC.

Purpose: Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation, with very poor outcomes. Herein, we evaluated ERBB2/HER2 expression in DSRCT as a therapeutic target.

Experimental design: ERBB2/HER2 expression was assessed in clinical samples and patient-derived xenografts (PDX) using RNA sequencing, RT-qPCR, and a newly developed HER2 IHC assay (clone 29D8). Responses to HER2 antibody-drug conjugates (ADC)-trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine-were evaluated in DSRCT PDX, cell line, and organoid models. Drug internalization was demonstrated by live microscopy. Apoptosis was evaluated by Western blotting and caspase activity assays.

Results: ERBB2/HER2 was detectable in DSRCT samples from patients and PDXs, with higher sensitivity RNA assays and improved IHC detectability using clone 29D8. Treatment of ERBB2/HER2-expressing DSRCT PDX, cell line, and organoid models with T-DXd or trastuzumab emtansine resulted in tumor regression. This therapeutic response was long-lasting in T-DXd-treated xenografts and was mediated by rapid HER2 ADC complex internalization and cytotoxicity, triggering p53-mediated apoptosis and growth arrest. Xenograft regression was associated with bystander payload effects triggering global tumor niche responses proportional to HER2 status.

Conclusions: ERBB2/HER2 is a therapeutic target in DSRCT. HER2 ADCs may represent novel options for managing this exceptionally aggressive sarcoma, possibly fulfilling an urgent and historically unmet need for more effective clinical therapy.

Gastrointestinal (GI) polyposis and cancer in pediatric patients is frequently due to an underlying hereditary cancer risk syndrome requiring ongoing cancer screening. Identification of at-risk patients through family history, clinical features of a syndrome, or symptom onset ensures appropriate cancer risk assessment and management in childhood and beyond. In this 2024 perspective, we outline updates to the hereditary GI cancer screening guidelines first published by the American Association of Cancer Research Pediatric Cancer Predisposition Workshop in 2017. These guidelines consider existing recommendations by pediatric and adult gastroenterology consortia to ensure alignment with gastroenterology practices in managing polyposis conditions. We specifically address the recommendations for pediatric screening in familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Further, we emphasize the importance of multidisciplinary care and partnership with gastroenterology, as it is crucial in management of children and families with these conditions.

Purpose: Interleukin (IL)-1 pathway upregulation is implicated in pancreatic ductal adenocarcinoma (PDAC) progression, therapy resistance, and survival. Nadunolimab is an IL-1 receptor accessory protein (IL1RAP)-targeting antibody with enhanced antibody-dependent cellular cytotoxicity that blocks IL-1α/IL-1β signaling. We investigated efficacy and safety of nadunolimab in PDAC, in combination with gemcitabine/nab-paclitaxel (GN).

Patients and methods: Patients with previously untreated locally advanced/metastatic PDAC received nadunolimab (1.0-7.5 mg/kg) every two weeks with standard GN. The primary objective was safety; secondary objectives were anti-tumor response, progression-free survival (PFS) and overall survival (OS). Correlations between serum and tumor biomarkers and clinical response were explored.

Results: 76 patients were enrolled, median age 63 years (range 43-89), 42% female, 97% with metastatic disease, 9% having received adjuvant chemotherapy. The most frequent Grade ≥3 adverse event was neutropenia (66%), typically during Cycle 1. Infusion-related reactions occurred in 29% (Grade 3, 3%). Only 1 of 76 patients had grade 3 or above peripheral neuropathy. No marked dose-dependent differences in safety or efficacy were observed between the four dose groups. Median OS overall was 13.2 months (95%CI 10.6-15.5) and 1-year survival was 58%. Median iPFS (iRECIST) was 7.2 months (95%CI 5.2-8.5). Treatment efficacy was higher in patients with high versus low tumor baseline IL1RAP expression (OS 14.2 vs 10.6 months, p=0.026). A reduction in serum IL-8 on treatment correlated with prolonged OS.

Conclusions: Nadunolimab combined with GN shows promising efficacy and manageable safety in locally advanced/metastatic PDAC. Higher tumor baseline IL1RAP expression correlated with better outcome.

Immunotherapies targeting the programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) checkpoint receptors have revolutionised the treatment of metastatic melanoma. However, half of treated patients do not respond to or eventually progress on standard therapies and many experience adverse events as a result of drug toxicity. The identification of accurate biomarkers of clinical outcomes are required in order to move away from the one-size-fits-all treatment approach of standard clinical practice, and towards a more personalised approach to enable the administration of the optimal therapy for any given patient and further improve patient outcomes. Recent clinical trials have proven the potential of multi-omics analyses, including genomic, gene expression, and tumour immune profiling, of patients' tumour biopsies, to predict a patient's response to subsequently administered immunotherapies. However, reproducibility of such multi-omics analyses, tissue requirements, and clinical validation have limited the practical application of these approaches in routine clinical workflows. In this review, we discuss several pivotal tissue-based profiling techniques that can be utilised to identify potential genomic, transcriptomic and immune biomarkers predictive of clinical outcomes following treatment with immune checkpoint inhibitors in melanoma. Furthermore, we highlight the key opportunities and challenges associated with the use of each of these techniques. The development and implementation of multimodal predictive models which combine data derived from these various methods is the future for achieving precision medicine for patients with melanoma.