JCO precision oncology最新文献

Purpose: The rapid expansion of precision oncology has led to a marked increase in the number of identified oncodriver genes and associated variants. This surge has elevated the frequency of mutations with unknown functional impact, highlighting the growing need for molecular modeling tools such as Swiss-PO to support variant interpretation for both clinical and research contexts.

Materials and methods: Swiss-PO was expanded and redesigned to integrate large-scale oncogenomic data with structure-based and sequence-based analytical tools. The platform combines data of oncodriver genes, multiple sequence alignment (MSA) for conservation analysis across orthologs and gene families, experimental and predicted three-dimensional (3D) structures prediction visualization to assess impacts of mutations. Additional modules include a BRAF kinase mutation classification model and a dedicated webpage for ligands targeting proteins, and unified integration with external databases to enable multidimensional analyses.

Results: The updated Swiss-PO platform integrates data for nearly 1,500 oncodriver genes, encompassing more than 3 million mutations and post-translational modification annotations, over 26,000 experimental and predicted 3D protein structures, more than 4,000 MSAs , and information on over 200,000 protein ligands. In addition, the platform includes a BRAF kinase mutation class predictor to support therapeutic decision-making, establishing Swiss-PO as one of the most comprehensive publicly available resources for precision oncology.

Conclusion: With these enhancements, Swiss-PO strengthens its role as a powerful and versatile resource for oncologists, bioinformaticians, and molecular biologists engaged in the interpretation of cancer-associated mutations and the advancement of precision medicine. The website is available at Swiss-PO.

Purpose: Cell surface-targeted therapies (CSTs) are a rapidly expanding class of cancer treatments with high specificity and reduced toxicity. Matching patients who express specific targets to CST clinical trials remains challenging because of complex eligibility criteria, diverse targets, and the absence of centralized, up-to-date trial databases. These gaps limit patient access and contribute to poor trial accrual.

Methods: We developed a large language model (LLM)-driven pipeline to identify and annotate CST clinical trials. Using a two-pronged approach, LLMs extracted target information from ClinicalTrials.gov and the National Cancer Institute Drug Database. Eight LLMs, including GPT-4o and several open-source models, were benchmarked against manually curated data sets of 814 CST trials and 814 non-CST trials. We evaluated model performance at target and trial levels and analyzed sources of error. We also provide an up-to-date database of open CST trials and their targets from the >100,000 total oncology clinical trials in ClinicalTrials.gov.

Results: GPT-4o achieved the highest accuracy in identifying CST trials (96.5%) and their targets (89.5%). Combining data sources improved performance, and accuracy increased with later trial phases. Most errors stemmed from vague therapy descriptions or string-matching issues. The model matched 94% of US trials and >95% of trials globally, with exceptions in China and New Zealand. In predicting cell surface localization, Gemma 3:27b and MedLlama3 correctly labeled all known clinical cell surface targets although performance varied beyond the most well-known CSTs.

Conclusion: Our LLM-based approach enables real-time, automated matching of patients to CST clinical trials, addressing major barriers to enrollment and expanding trial accessibility. Errors were uncommon, and performance is poised to improve as LLMs evolve. Optimizing patient-trial matching for CSTs can improve both patient benefit and trial success.

Purpose: MYCN amplification (MYCN-A) is an important prognostic marker in neuroblastoma. However, the impact of MYCN-A in patients with metastasized high-risk neuroblastoma during the course of disease remains unclear. The aim of this study was to investigate response and relapse patterns of stage IV patients with and without amplification of MYCN.

Materials and methods: Amplification of the MYCN oncogene was assessed by fluorescence in situ hybridization, whole exome sequencing, or single nucleotide polymorphism analysis. Complete remission (according to the revised International Neuroblastoma Response Criteria) and survival outcomes were estimated.

Results: Among the 164 patients older than 12 months with metastatic high-risk neuroblastoma, 50 (30%) had MYCN-A. MYCN-A was a significant prognostic marker for overall survival (P = .04). Patients with MYCN-amplified tumors reached complete remission faster compared with those without MYCN amplification (HR, 1.8 [95% CI, 1.2 to 2.8]; P < .01). MYCN-A was associated with recurrence when evaluated from diagnosis and after induction treatment (HR, 1.6 [95% CI, 1.0 to 2.4]; and HR, 1.8 [95% CI, 1.1 to 2.8], respectively), as well as to the cumulative incidence of recurrence (P = .04 and P = .03, respectively). SIOPEN scores detected on meta-[¹²³I]iodobenzylguanidine (MIBG) scintigraphy were significantly lower in patients with MYCN-amplified tumors than in patients with MYCN nonamplified tumors at diagnosis and after induction treatment (P < .01 and P = .01, respectively). From end of induction, MYCN-A stratified by SIOPEN score was associated with the cumulative incidence of recurrence (P < .01).

Conclusion: Despite achieving complete remission faster, patients with MYCN-A have a higher probability of recurrence compared with those without MYCN-A.

Purpose: Fanconi anemia (FA) is a genetic disorder typically characterized by progressive bone marrow failure (BMF) during childhood, leading to diagnosis at that stage. In adolescence or adulthood, patients are predisposed to myelodysplastic syndrome (MDS), acute myeloid leukemia, and solid tumors. However, some individuals present atypically, delaying FA recognition and resulting in life-threatening complications. This study describes the distinctive phenotype associated with biallelic FANCM pathogenic variants.

Patients and methods: Clinical and biologic data were analyzed from eight patients carrying biallelic germline FANCM pathogenic variants within a French cohort of 411 patients with FA (2.0%). Clinical outcomes were compared with those of patients with FA carrying non-FANCM variants.

Results: None of the eight FANCM patients developed BMF, contrasting with a 93.5% cumulative incidence among other FA genotypes (P < .0001). This absence of marrow failure resulted in delayed FA diagnosis (median age 23.5 v 6.8 years, P < .01). Instead, six patients initially presented with malignancy and exhibited marked toxicity to conventional cancer therapies, prompting FA testing. Malignancies included four oral cancers and, unexpectedly, two ALL: a ZNF384-rearranged B-cell precursor ALL and a BCL11B::HOXA13 early T-cell precursor ALL. No ALL cases occurred among the 403 non-FANCM patients with FA (P < .0001). The treatment courses of the two FANCM-related ALL cases are reported.

Conclusion: Biallelic FANCM variants define a distinct FA subtype lacking early BMF, leading to missed diagnoses and severe toxicity upon malignancy. Recognizing this presentation is crucial for timely FA detection and for implementing adapted therapeutic and follow-up strategies.

Purpose: Gastroesophageal carcinoma (GEC) is increasingly managed using biomarker-guided therapies. Although both tissue DNA (tDNA) and circulating tumor DNA (ctDNA) testing are used clinically, the concordance of genomic alterations between primary tumors, metastatic sites, and liquid biopsy remains incompletely understood.

Methods: We retrospectively analyzed 345 patients with GEC who underwent ctDNA testing at Mayo Clinic. tDNA next-generation sequencing and immunohistochemistry (IHC) for human epidermal growth factor receptor 2 (HER2)/erb-b2 receptor tyrosine kinase 2 (ERBB2) and mismatch repair (MMR) were collected. Concordance was evaluated between ctDNA and tDNA, ctDNA and IHC, and across all three modalities, using 60-day and 30-day intervals.

Results: Among 345 patients with ctDNA testing, 186 had tDNA testing, and 310 underwent IHC. ctDNA testing showed a shorter turnaround time than tDNA (median 6 v 13 days). The most frequent alteration in ctDNA, primary tDNA, and metastatic tDNA was TP53. Concordance between ctDNA and primary tDNA was ≥78.8% for key genes; between ctDNA and metastatic tDNA, it was ≥84.8%. IHC-ctDNA concordance was higher in metastatic tumors, with 91.1% for HER2/ERBB2 and 97.7% for mismatch repair (MMR)/microsatellite instability (MSI) compared with 81.1% and 95.8%, respectively, in primary tumors. Triplet concordance for MSI/MMR was 97.6% in primary tumors and 100% in metastatic tumors, while ERBB2/HER2 showed 84.4% and 93.9% concordance, respectively. ctDNA temporal heterogeneity analysis revealed 14 patients with fluctuating ERBB2 status and 3 with fluctuating MSI-H status.

Conclusion: ctDNA testing demonstrates high concordance with tDNA and IHC and offers faster turnaround. Given its minimally invasive nature and strong concordance with tissue-based testing, ctDNA is a reliable tool for genomic profiling and longitudinal monitoring in GEC.

Purpose: Routine confirmatory testing of p16+ oropharyngeal cancers (OPCs) for human papillomavirus (HPV) mRNA is nonstandard despite evidence that negative confirmatory tests are common and may indicate poor prognosis. This study aimed to evaluate the utility of confirmatory testing by assessing the etiologies and prognostic significance of negative HPV mRNA tests in a surgically treated cohort of p16+ OPCs enriched for recurrence-prone tumors.

Methods: Fifty tumors that later recurred (cases) and 50 cured tumors (controls) were matched for key clinical features. Patients were predominantly White males with a median age of 62 years. Confirmatory testing was performed with a clinically used E6/E7 RNA in situ hybridization assay (RNAScope). RNA sequencing (RNAseq) was used to define true HPV positivity and profile HPV mRNA levels. HPV genotypes and integration were evaluated by sequencing HPV DNA and detecting HPV-host fusion mRNAs, respectively.

Results: Positive p16 was 100% specific for high-risk HPV mRNA expression. Content of HPV types, lineages, and sublineages did not differ significantly between cases and controls. Cases contained more frequent HPV integration based on increased HPV-host mRNA fusions (P < .0007). False-negative confirmatory assays, which occurred in 6% (n = 6) of the cohort, were equally distributed between groups and not prognostic of survival. False negatives included three tumors containing HPV types absent from the RNAScope probe set and an episomal tumor with E6/E7 mRNA below the detection threshold by RNAseq.

Conclusion: HPV RNAScope appears unlikely to detect HPV status misclassification or be prognostic in typical p16+ OPCs treated surgically in the United States. Confirmatory RNAScope can produce misleading false negatives in this population through various mechanisms and should be used selectively rather than routinely.

Purpose: Although the clinicopathologic features of BRAF/NRAS-mutant melanoma are well defined, the molecular landscape, clinicopathologic features, and treatment outcomes of BRAF/NRAS wild-type (WT) patients on immune checkpoint inhibitors (ICIs) remain less clear. The MatchMEL study investigated the mutational profile of WT melanoma (Part 1) and examined whether targeted treatments could be matched to specific molecular alterations with clinical activity (Part 2). We report findings from Part 1 only, focusing on the genomic landscape and clinicopathologic correlates in ICI-treated patients.

Methods: In Part 1, consecutive patients with advanced melanoma at two Australian centers were enrolled. BRAF/NRAS WT patients underwent FoundationOneCDx (F1CDx) sequencing. Clinical, pathologic, and treatment data were collected. Patients were stratified by mutational status (BRAF, NRAS, NF1, triple WT), and associations between tumor mutational burden (TMB), overall response rates (ORR), and survival outcomes (progression-free survival [PFS]) were analyzed using logistic regression and Kaplan-Meier methods. A molecular tumor board analyzed F1CDx results to match targeted therapy to molecular alterations. Part 2 assessed outcomes for patients treated with matched targeted therapies.

Results: From 2021 to 2023, 210 patients were enrolled. Fifty-seven (27%) had BRAF V600 mutation, 53 (25%) had NRAS mutation, and 100 (48%) were BRAF/NRAS WT. Of these, 86 underwent profiling; NF1 mutations were detected in 37 (43%) and were associated with the highest median TMB (53 mut/Mb). NF1-mutant melanoma had a numerically longer median PFS (26.8 months [95% CI, 20.2 to not reached]; P = .58) and higher ORR (63%; P = .67) to first-line ICIs than other subtypes.

Conclusion: Our findings suggest significant clinical, pathologic, and molecular correlations in an Australian cohort of advanced melanoma treated with ICIs. Patients with NF1 mutation exhibited higher TMB, which was associated with improved response to ICIs.

Purpose: BRCA1 promoter methylation (BRCA1meth) affects 20%-27% of triple-negative breast cancer (TNBC) and ovarian cancer (OvCa) and has therapeutic predictive value in both cancer types. BRCA1meth is established during early embryonic development as a constitutional event, and its detection in the peripheral blood cells of unaffected women associates with increased risk for breast cancer and OvCa. Thus, facile and sensitive assessment of BRCA1meth is an important component for both risk assessment and the therapeutic management of these cancer types.

Methods: We used the GRAIL circulating cell-free DNA (cfDNA)-based targeted methylation platform to quantify BRCA1meth in cfDNA (cfBRCA1meth) from plasma samples of individuals with and without cancer.

Results: Detection of cfBRCA1meth was accurate and sensitive, with an empirical LoD₉₅ of 0.0081. cfBRCA1meth was found in 4.1% (113/2,790) of individuals without cancer, and it was significantly more prevalent in females compared with males (4.8% v 2.9%, P = .016), suggesting that the dynamics of BRCA1 promoter methylation and its consequences for cancer development may differ by sex. In a pan-cancer cohort comprising 2,849 patients and representing 15 tissue types, cfBRCA1meth was enriched only in TNBC (15.2%, P = .001) and OvCa (13.9%, P = .014). Importantly, in these cfBRCA1meth-positive cases, the fraction of cfBRCA1meth was correlated with a methylation-based estimate of tumor burden.

Conclusion: Our findings demonstrate that BRCA1meth can be robustly detected using cfDNA assessment both as a constitutional event in noncancer samples and as a metric of BRCA1meth tumor burden in individuals with BRCA1meth cancers. Therefore, the GRAIL assay provides a single quantitative platform that can be used to explore the role of BRCA1meth in cancer risk and therapeutic response.

Purpose: Comprehensive genomic profiling (CGP) is strongly advocated by organizations like ASCO and National Comprehensive Cancer Network (NCCN) to tailor precision-guided therapies for patients with cancer. However, these guidelines often lack specificity regarding panel size or essential features required within CGP panels.

Materials and methods: A pilot pan-cancer study of patients (N = 85) treated in a value-based community health care setting who received next-generation sequencing (NGS)-based CGP from Tempus AI, Inc and an expanded analysis of de-identified patient records from the Tempus database (N = 465) for patients treated within a community health care network. Rates of potentially actionable findings defined as variants matching US Food and Drug Administration -approved therapies (somatic variants/resistance markers, Tumor Mutational Burden high [TMB-H] or Microsatellite Instability high [MSI-H]), or identification of pathogenic/likely pathogenic germline findings. Enrollment in clinical trials was included in the expanded cohort.

Results: In our pilot cohort, potentially actionable alterations were detected in 49% of patients (n = 42). Of them, 12% (n = 5) of patients had a finding that was identified only by advanced features-including tumor-normal match, RNA sequencing, and/or liquid biopsy reflex testing-and may have been missed by the existing in-network NGS options. In the expanded cohort, potentially actionable alterations were detected in 31% (n = 146) of patients. Of them, 12% (n = 17) had findings identified solely by advanced features, including three patients enrolled in clinical trials.

Conclusion: This study indicates that the CGP expanded treatment options in both the pilot and expanded cohort, with improvements directly attributable to specific features like tumor-normal matching, liquid biopsy reflex ordering, RNA sequencing, and Just-in-Time clinical trial matching.