Using Advanced Molecular Profiling to Identify the Origin of and Tailor Treatment for an Intracranial Mass of Unknown Primary.
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ABSTRACT:
SUBMITTER: Martinez F
PROVIDER: S-EPMC8202556 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:MicroRNA expression data (Agilent miRNA microarray v.2) obtained for 101 FFPE samples of primary and metastatic tumors.
| S-ECPF-TABM-1135 | biostudies-other
Project description:BackgroundCarcinoma of unknown primary origin (CUP) accounts for 2%-5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm.Materials and methodsCentrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture-based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death-ligand 1 (PD-L1) positivity were determined.ResultsA total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ≥16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD-L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%.ConclusionsThirty-two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD-L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP-informed treatment. Clinical trial identification number. NCT03498521 IMPLICATIONS FOR PRACTICE: The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death-ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling-informed treatment.
| S-EPMC7930409 | biostudies-literature
Project description:Cancer of unknown primary (CUP) represents a common and important clinical problem. There is evidence that most CUPs are metastases of carcinomas whose primary site cannot be recognized. Driven by the hypothesis that the knowledge of primary cancer could improve patient's prognosis, we investigated microRNA expression profiling as a tool for identifying the tissue of origin of metastases. We assessed microRNA expression from 101 formalin-fixed, paraffin-embedded (FFPE) samples from primary cancers and metastasis samples by using a microarray platform. Forty samples representing ten different cancer types were used for defining a cancer-type-specific microRNA signature, which was used for predicting primary sites of metastatic cancers. A 47-miRNA signature was identified and used to estimate tissue-of-origin probabilities for each sample. Overall, accuracy reached 100% for primary cancers and 78% for metastases in our cohort of samples. When the signature was applied to an independent published dataset of 170 samples, accuracy remained high: correct prediction was found within the first two options in 86% of the metastasis cases (first prediction was correct in 68% of cases). This signature was also applied to predict 16 CUPs. In this group, first predictions exhibited probabilities higher than 90% in most of the cases. These results establish that FFPE samples can be used to reveal the tissue of origin of metastatic cancers by using microRNA expression profiling and suggest that the approach, if applied, could provide strong indications for CUPs, whose correct diagnosis is presently undefined.
| S-EPMC4325368 | biostudies-literature
Project description:Cancer of unknown primary (CUP), in which metastatic diseases exist without an identifiable primary location, accounts for about 3-5% of all cancer diagnoses. Successful diagnosis and treatment of such patients are difficult. This study aimed to assess the expression characteristics of 90 genes as a method of identifying the primary site from CUP samples. We validated a 90-gene expression assay and explored its potential diagnostic utility in 44 patients at Jiangsu Cancer Hospital. For each specimen, the expression of 90 tumor-specific genes in malignant tumors was analyzed, and similarity scores were obtained. The types of malignant tumors predicted were compared with the reference diagnosis to calculate the accuracy. In addition, we verified the consistency of the expression profiles of the 90 genes in CUP secondary malignancies and metastatic malignancies in The Cancer Genome Atlas. We also reported a detailed description of the next-generation coding sequences for CUP patients. For each clinical medical specimen collected, the type of malignant tumor predicted and analyzed by the 90-gene expression assay was compared with its reference diagnosis, and the overall accuracy was 95.4%. In addition, the 90-gene expression profile generally accurately classified CUP into the cluster of its primary tumor. Sequencing of the exome transcriptome containing 556 high-frequency gene mutation oncogenes was not significantly related to the 90 genes analysis. Our results demonstrate that the expression characteristics of these 90 genes can be used as a powerful tool to accurately identify the primary sites of CUP. In the future, the inclusion of the 90-gene expression assay in pathological diagnosis will help oncologists use precise treatments, thereby improving the care and outcomes of CUP patients.
| S-EPMC8529103 | biostudies-literature
Project description:BackgroundDetermining the tissue of origin (TOO) is essential for managing cancer of unknown primary (CUP). In this study, we evaluated the concordance between genome profiling and DNA methylation analysis in determining TOO for lung-specific CUP and assessed their performance by comparing the clinical responses and survival outcomes of patients predicted with multiple primary or with metastatic cancer.MethodsWe started by retrospectively screening for CUP patients who presented with both intra- and extrathoracic tumors. Tumor samples from included patients were analyzed with targeted sequencing with a 520-gene panel and targeted bisulfite sequencing. TOO inferences were made in parallel via an algorithm using genome profiles and time interval between tumors and via machine learning-based classification of DNA methylation profiles.ResultsFour hundred patients were screened retrospectively. Excluding patients definitively diagnosed with conventional diagnostic work-up or without available samples, 16 CUP patients were included. Both molecular approaches alone enabled inference of clonality for all analyzed patients. Genome profile enabled TOO inference for 43.8% (7/16) patients, and the percentage rose to 68.8% (11/16) after considering inter-tumor time lag. On the other hand, DNA methylation analysis was conclusive for TOO prediction for 100% (14/14) patients with available samples. The two approaches gave 100% (9/9) concordant inferences regarding clonality and TOO identity. Moreover, patients predicted with metastatic disease showed significantly shorter overall survival than those with multiple primary tumors.ConclusionsGenome and DNA methylation profiling have shown promise as individual analysis for TOO identification. This study demonstrated the feasibility of incorporating the two methods and proposes an integrative scheme to facilitate diagnosing and treating lung-specific CUPs.
| S-EPMC8981640 | biostudies-literature
Project description:INTRODUCTION:Management of patients with intracranial metastases from an unknown primary tumor (CUP) varies compared to those with metastases of known primary tumor origin (CKP). The National Institute for Health and Care Excellence (NICE) recognizes the current lack of research to support the management of CUP patients with brain metastases. The primary aim was to compare survival outcomes of CKP and CUP patients undergoing early resection of intracranial metastases to understand the efficacy of surgery for patients with CUP. METHODS:A retrospective study was performed, wherein patients were identified using a pathology database. Data was collected from patient notes and trust information services. Surgically managed patients during a 10-year period aged over 18 years, with a histological diagnosis of intracranial metastasis, were included. RESULTS:298 patients were identified, including 243 (82.0%) CKP patients and 55 (18.0%) CUP patients. Median survival for CKP patients was 9 months (95%CI 7.475-10.525); and 6 months for CUP patients (95%CI 4.263-7.737, p?=?0.113). Cox regression analyses suggest absence of other metastases (p?=?0.016), age (p?=?0.005), and performance status (p?=?0.001) were positive prognostic factors for improved survival in cases of CUP. The eventual determination of the primary malignancy did not affect overall survival for CUP patients. CONCLUSIONS:There was no significant difference in overall survival between the two groups. Surgical management of patients with CUP brain metastases is an appropriate treatment option. Current diagnostic pathways specifying a thorough search for the primary tumor pre-operatively may not improve patient outcomes.
| S-EPMC7392948 | biostudies-literature
Project description:Numerous investigations have been conducted using molecular profiling to evaluate the possible clonal origin of second malignancies in various cancer types. However, to date no study assessing clonality of multiple primaries has been conducted in melanoma. In this investigation using patients treated at a specialist melanoma treatment center, we compared the somatic mutational profiles of pairs of melanomas designated as independent on the basis of thorough assessment of their clinical and pathologic characteristics. We used a set of highly polymorphic genetic markers selected on the basis of their chromosomal positions and the frequencies of reported allelic losses at these genetic loci. Our statistical testing strategy showed no significant evidence of clonal origin of the two primaries in 17 of the 19 patients examined. The results suggest that most second melanomas designated as independent primary tumors on the basis of their clinicopathologic features are indeed independent occurrences of the disease, supporting the validity of the criteria used by experienced pathologists in distinguishing new primaries from metastases.
| S-EPMC2745834 | biostudies-literature
Project description:Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments; however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18-class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for high-medium confidence predictions. Classification performance was similar in clinicopathology-resolved CUPs - 80% had high-medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology-unresolved CUPs had high-medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology-unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours were another identifiable subset. In conclusion, DNA and RNA profiling supported an unconfirmed TOO diagnosis in one-third of CUPs otherwise unresolved by clinicopathology assessment alone. DNA mutation profiling was the more diagnostically informative assay. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
| S-EPMC10099529 | biostudies-literature
Project description:Background: Fatal cancer is often the result of spread, or metastasis, of a cancer cell from the site of its origin to a distant anatomic site. While the metastatic process and the foreign environment of the metastatic site impact a tumor’s biology, we continue to determine therapy for patients based upon their cancer’s site of origin. We have performed an unbiased analysis across metastatic solid tumors from common primary sites to determine the molecular impact of the metastatic process on site-specific biology and to identify novel therapeutic strategies. Methods: Global gene expression was used as a biological phenotype to perform a top-down analysis of 96 metastatic human tumors. Laser capture microdissection, RNA amplification, and microarray analysis were used to measure the transcription patterns of malignant epithelial cells. Genes, multi-gene expression “signatures”, and pathways associated with site of origin (SOO) and site of metastases (SOM) were identified using established computational approaches. SOO and SOM expression signatures were validated on multiple, independent datasets comprising 1217 samples (1104 samples from GSE2109 (Expression Project for Oncology) and 113 samples from GSE12630 (Monzon FA, Lyons-Weiler M, Buturovic LJ, Rigl CT et al. Multicenter validation of a 1,550-gene expression profile for identification of tumor tissue of origin. J Clin Oncol 2009 May 20;27(15):2503-8. PMID: 19332734). Reverse phase proteomics and in vitro tissue culture were used to validate associations between biological pathways, site of primary, and implicated therapeutic combinations. Findings: SOO has the dominant influence on solid tumor biology as samples segregate based upon their primary site during unsupervised hierarchical clustering. In addition, statistically significant associations are identified between single genes and pathways and each primary site investigated and SOO signatures for colon, breast, ovary, lung, and prostate cancers accurately identify primary site for independent samples of both local and metastatic tumors independent of degree of histological differentiation. The impact of SOM on tumor biology is evident as genes and pathways are significantly associated with metastatic site and SOM signatures can be generated but they are not strongly predictive when applied to localized tumors. Pathway analysis identified relatively increased expression of MYC, beta-catenin, and SRC gene sets in metastatic colorectal cancers which was confirmed with proteomic analysis of a sub-set of the original tumors. Within colorectal cancers, high SRC expression also correlates with predicted oxaliplatin sensitivity and the combination of an SRC inhibitor with oxaliplatin demonstrated synergy in three independent colorectal cancer cell lines. Interpretation: Our findings suggest that the complex alterations required for metastasis do not obscure the impact of a cancer cell’s origin. SOO signatures have the potential to be highly accurate diagnostic tools and the underlying site-specific biology can be used to identify novel therapeutic targets for advanced cancers. Keywords: Gene expression analysis
2016-02-13 | GSE18549 | GEO
Project description:Cancer of unknown primary (CUP) site poses diagnostic challenges due to its elusive nature. Many cases of CUP manifest as pleural and peritoneal serous effusions. Leveraging cytological images from 57,220 cases at four tertiary hospitals, we developed a deep-learning method for tumor origin differentiation using cytological histology (TORCH) that can identify malignancy and predict tumor origin in both hydrothorax and ascites. We examined its performance on three internal (n = 12,799) and two external (n = 14,538) testing sets. In both internal and external testing sets, TORCH achieved area under the receiver operating curve values ranging from 0.953 to 0.991 for cancer diagnosis and 0.953 to 0.979 for tumor origin localization. TORCH accurately predicted primary tumor origins, with a top-1 accuracy of 82.6% and top-3 accuracy of 98.9%. Compared with results derived from pathologists, TORCH showed better prediction efficacy (1.677 versus 1.265, P < 0.001), enhancing junior pathologists' diagnostic scores significantly (1.326 versus 1.101, P < 0.001). Patients with CUP whose initial treatment protocol was concordant with TORCH-predicted origins had better overall survival than those who were administrated discordant treatment (27 versus 17 months, P = 0.006). Our study underscores the potential of TORCH as a valuable ancillary tool in clinical practice, although further validation in randomized trials is warranted.
| S-EPMC11108774 | biostudies-literature