Clinical Cancer Research

BackgroundNeoadjuvant chemotherapy (NAC) is the standard of care for locally advanced breast cancer. However, the disconnect between efficacy in randomized trials and effectiveness in real-world practice--attributable to real-world treatment delays and adherence barriers--remains underexplored for early-stage (cT1-cT3) operable disease. MethodsWe applied the Target Trial Emulation (TTE) framework to a propensity-score matched cohort from the SEER database. To mitigate immortal time bias and sta...

PurposeCirculating tumor DNA (ctDNA) analyses are informative as an early indicator of immunotherapy response in advanced non-small cell lung cancer (NSCLC); however, the clinical value of ctDNA molecular response requires further validation. Patients and MethodsAs part of a prospective clinical protocol (NCT05995821), we conducted targeted error-correction sequencing of ctDNA (n=328) and matched WBC DNA (n=109) from 109 patients with metastatic NSCLC who received anti-PD-(L)1 either as monothe...

BackgroundMeningioma-induced hyperostosis (MIH) is a frequent radiographic finding, yet its underlying mechanisms remain poorly understoodWhile hyperostosis has traditionally been treated as a binary phenomenon, the aim of this study was to determine whether MIH represents a heterogenous process with distinct radiological subtypes associated with genetic associations. MethodsWe retrospectively reviewed the records and imaging of patients with meningiomas resected between 2021-2024 at a single i...

We previously reported initial results from a clinical trial testing a strategy in which patients with muscle-invasive bladder cancer (MIBC) achieving a clinical complete response after cystoscopic resection of the bladder tumor plus systemic therapy could forgo removal of their entire bladder (cystectomy). While the results were highly promising, a subset of patients omitting initial cystectomy developed recurrence highlighting the need for biomarkers to refine selection of patients for this ap...

Multiple myeloma (MM) evolves from monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) with annual progression rates of 1% and 10%, respectively. Current risk models dont fully capture the underlying dynamic molecular processes. We hypothesized that urinary peptides reflect disease-specific microenvironmental alterations in plasma cell dyscrasias. To test this hypothesis, capillary electrophoresis-mass spectrometry CE-MS was applied to profile the urinary peptidome ...

BackgroundIn immune checkpoint inhibitor (ICI) trials, overall survival (OS) benefits are well established, yet improvements in quality of life (QoL) are often inconsistent or absent in conventional analyses. This apparent discordance raises important questions: are QoL outcomes truly unrelated to survival, and how can QoL results be better utilized and interpreted? MethodsA model-based meta-analysis (MBMA) of longitudinal EORTC QLQ-C30 global health status/quality of life data from randomized ...

BackgroundImmune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC), yet primary resistance remains common, with only [~]50% of patients responding to first-line chemo-immunotherapy and 20-30% to monotherapy. Existing biomarkers such as PD-L1 expression and Tumor Mutational Burden (TMB) demonstrate limited predictive accuracy, underscoring the need for more comprehensive, integrative approaches. MethodsWe conducted a prospective...

ObjectiveCervical cancer is caused by human papillomavirus (HPV) infections; however, there are no molecularly defined subtypes, and few approved targeted therapies. We defined molecular subtypes and tested targeted agents. MethodsPublic datasets were analyzed; cell lines were treated with drugs; and donor T cells and their proliferation were measured. ResultsWe define three molecular subtypes: I, Wild type for PIK3CA/no YAP1 amplification; II, PIK3CA mutation/no YAP1 amplification; III, PIK3C...

BackgroundPATZ1 fusion-positive central nervous system (CNS) tumors frequently harbor MN1::PATZ1 fusions as driver mutations, provisionally classified as a rare DNA methylation class of low-grade neuroepithelial tumors. Radiographically, they resemble pilocytic astrocytomas with tumor and cystic components, but their supratentorial cortex location and higher recurrence rates are distinguishing features. An intermediate clinical course, despite focal high-grade histopathology, underscores the nee...

DNA repair capacity (DRC), particularly at the pathway level, varies among individuals. While previous studies explored DRC in relation to environmental exposures and cancer risk, few measured DRC in patient-focused cohorts and were focused on one or two repair pathways only. We comprehensively profiled DRC for all the major repair pathways and DNA lesions in 100 lung cancer patients undergoing radiotherapy (RT) using advanced Fluorescence Multiplex based Host Cell Reactivation assays in blood c...

PurposePrognosis in metastatic non-seminomatous germ cell tumors (mNSGCT) is currently guided by the IGCCCG classification, which incorporates tumor markers, organs involved with metastatic disease, and primary site but not histologic subtype. We aimed to evaluate whether specific histological components provide additional prognostic information in a large international mNSGCT cohort. Patient and MethodsWe analyzed clinical, pathologic, and outcome data from 662 patients with mNSGCT across mult...

BackgroundGlioblastoma (GBM) represents an aggressive malignancy with limited therapeutic options. The immunosuppressive nature of GBM may be reversible with immune checkpoint inhibitor (ICI) treatment, however, initial studies have yet to demonstrate this. It is postulated that trafficking of peripherally activated lymphocytes may play a role in generating a robust intracranial immune response. Therefore, a blood-based assay to identify peripheral blood response may both predict response and be...

BackgroundImmune checkpoint inhibition has transformed cancer therapy; however, many patients fail to respond to single-agent blockade, and combination strategies are often limited by toxicity. Central nervous system tumors exploit multiple immunosuppressive pathways, including the CD200 and PD-1/PD-L1 axis to evade anti-tumor immunity and support tumor aggressiveness. MethodsWe investigated ARL200, a peptide ligand targeting the CD200 activation receptor (CD200AR) using in vitro immune assays,...

BackgroundA retrospective study in Nature recently reported improved overall survival (OS) when COVID-19 mRNA vaccination was administered around initiation of immune checkpoint inhibitor (ICI) therapy. Whether this association depends on vaccination timing relative to ICI treatment remains unclear. MethodsWe conducted a single-centre retrospective cohort study of patients receiving palliative-intent ICI therapy at a UK tertiary cancer centre (October 2014-December 2025). Two vaccination exposu...

Metastatic pancreatic ductal adenocarcinoma (PDAC) remains deadly, with minimal improvement in prognosis over the past 20 years despite expansion of our chemotherapeutic arsenal. The complex tumor microenvironment (TME) of PDAC in the advanced stage, which often accompany clinical diagnosis, likely contributes to the limited efficacy of current standard of care chemotherapy. Informed by mechanistic preclinical studies, we evaluated the impact of inhibition of Hedgehog (Hh) signaling to prime PDA...

Structured AbstractO_ST_ABSPurpose/ObjectivesC_ST_ABSThe role of postmastectomy radiotherapy (PMRT) in patients with pathologic N1 (pN1) breast cancer, including triple-negative breast cancer (TNBC), remains controversial in the era of modern systemic therapy. We evaluated the association between PMRT and recurrence-free survival (RFS) and overall survival (OS) and identified prognostic factors in a contemporary single-institution pN1 cohort. Materials/MethodsWe retrospectively reviewed female ...

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with high mortality rates, often exhibiting resistance to conventional treatments such as radiotherapy (RT) or a combination of chemotherapy and radiotherapy (CRT). The nerve growth factor receptor (NGFR, also known as p75NTR or CD271) is a well-established cancer stem cell marker in melanoma, where it has been linked to resistance to multiple therapies. In HNSCC, NGFR has been reported as a poor prognostic marker, with it...

Background and ObjectivePatients with upper urinary tract urothelial carcinoma (UTUC) undergoing radical surgery are at high risk of developing intravesical recurrences (IVR). The biology of IVR after surgery for UTUC is poorly understood, and urine markers to replace cystoscopic surveillance of the bladder are lacking. Here, we characterized the genomic landscape of UTUC and paired IVR to discover therapeutic targets and identify diagnostic markers for IVR. MethodsWe performed targeted next-ge...

BackgroundGenomic assays such as Oncotype DX, MammaPrint, and Prosigna have transformed risk stratification and treatment selection in early-stage, estrogen receptor-positive (ER+), HER2-negative breast cancers by enabling more precise prognostication and chemotherapy de-escalation in selected patients. However, their clinical utility is limited in lymph nodes positive disease. A major unmet need is the development of compact, mechanistically grounded biomarkers that extend risk and treatment-re...

Pediatric solid high-risk malignancies mostly lack established molecular biomarkers for early detection, minimal residual disease assessment, or treatment monitoring. Challenges include small patient numbers, limited sample volumes, low tumor mutational burden, and few recurrent alterations. Within the prospective multicenter pediatric precision oncology program INFORM, we collected liquid biopsies from 130 pediatric patients and optimized cfDNA isolation and analysis. Whole-genome, whole-exome,...