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Diagnostic Accuracy of PIK3CA Mutation Detection by Circulating Free DNA in Breast Cancer: A Meta-Analysis of Diagnostic Test Accuracy.

ABSTRACT: Mutation of p110 alpha-catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) has high predictive and prognostic values for breast cancer. Hence, there has been a marked interest in detecting and monitoring PIK3CA genotype with non-invasive technique, such as circulating free DNA (cfDNA). However, the diagnostic accuracy of PIK3CA genotyping by cfDNA is still a problem of controversy. Here, we conducted the first meta-analysis to evaluate overall diagnostic performance of cfDNA for PIK3CA mutation detection. Literature search was performed in Pubmed, Embase and Cochrane Central Register of Controlled Trials databases. Seven cohorts from five studies with 247 patients were included. The pooled sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio and area under summary receiver operating characteristic curve were calculated for accuracy evaluation. The pooled sensitivity and specificity were 0.86 (95% confidence interval [CI] 0.32-0.99) and 0.98 (95% CI 0.86-1.00), respectively; the pooled positive and negative likelihood ratio were 42.8 (95% CI 5.1-356.9) and 0.14 (95% CI 0.02-1.34), respectively; diagnostic odds ratio for evaluating the overall diagnostic performance was 300 (95% CI 8-11867); area under summary receiver operating characteristic curve reached 0.99 (95% CI 0.97-0.99). Subgroup analysis with metastatic breast cancer revealed remarkable improvement in diagnostic performance (sensitivity: 0.86-0.91; specificity: 0.98; diagnostic odds ratio: 300-428). This meta-analysis proved that detecting PIK3CA gene mutation by cfDNA has high diagnostic accuracy in breast cancer, especially for metastatic breast cancer. It may serve as a reliable non-invasive assay for detecting and monitoring PIK3CA mutation status in order to deliver personalized and precise treatment.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC4918940 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBreast cancer (BC) is the most frequently diagnosed cancer among women. Numerous studies explored cell-free circulating microRNAs as diagnostic biomarkers of BC. As inconsistent and rarely intersecting microRNA panels have been reported thus far, we aim to evaluate the overall diagnostic performance as well as the sources of heterogeneity between studies.MethodsBased on the search of three online search engines performed up to March 21st 2022, 56 eligible publications that investigated diagnostic circulating microRNAs by utilizing Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) were obtained. Primary studies' potential for bias was evaluated with the revised tool for the quality assessment of diagnostic accuracy studies (QUADAS-2). A bivariate generalized linear mixed-effects model was applied to obtain pooled sensitivity and specificity. A novel methodology was utilized in which the sample and study models' characteristics were analysed to determine the potential preference of studies for sensitivity or specificity.ResultsPooled sensitivity and specificity of 0.85 [0.81-0.88] and 0.83 [0.79-0.87] were obtained, respectively. Subgroup analysis showed a significantly better performance of multiple (sensitivity: 0.90 [0.86-0.93]; specificity: 0.86 [0.80-0.90]) vs single (sensitivity: 0.82 [0.77-0.86], specificity: 0.83 [0.78-0.87]) microRNA panels and a comparable pooled diagnostic performance between studies using serum (sensitivity: 0.87 [0.81-0.91]; specificity: 0.83 [0.78-0.87]) and plasma (sensitivity: 0.83 [0.77-0.87]; specificity: 0.85 [0.78-0.91]) as specimen type. In addition, based on bivariate and univariate analyses, miRNA(s) based on endogenous normalizers tend to have a higher diagnostic performance than miRNA(s) based on exogenous ones. Moreover, a slight tendency of studies to prefer specificity over sensitivity was observed.ConclusionsIn this study the diagnostic ability of circulating microRNAs to diagnose BC was reaffirmed. Nonetheless, some subgroup analyses showed between-study heterogeneity. Finally, lack of standardization and of result reproducibility remain the biggest issues regarding the diagnostic application of circulating cell-free microRNAs.

Project description:BackgroundThe circulating tumor DNA (ctDNA) diagnostic accuracy for detecting phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations in breast cancer (BC) is under discussion. We aimed to compare plasma and tissue PIK3CA alterations, encompassing factors that could affect the results.MethodsTwo reviewers selected studies from different databases until December 2020. We considered BC patients with matched tumor tissue and plasma ctDNA. We performed meta-regression and subgroup analyses to explore sources of heterogeneity concerning tumor burden, diagnostic technique, sample size, sampling time, biological subtype, and hotspot mutation. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the related area under the curve (AUC) were elaborated for the overall population and each subgroup.ResultsThe pooled analysis was carried out on 25 cohorts for a total of 1966 patients. The overall ctDNA sensitivity and specificity were 0.73 (95% CI: 0.70-0.77) and 0.87 (95% CI: 0.85-0.89). The AUC was 0.93. Pooled concordance, negative predictive value and positive predictive value values were 0.87 (95% CI: 0.82-0.92), 0.86 (95% CI: 0.81-0.90), and 0.89 (95% CI: 0.81-0.95) with pooled PLR, NLR, and DOR of 7.94 (95% CI: 4.90-12.86), 0.33 (95% CI: 0.25-0.45), and 33.41 (95% CI: 17.23-64.79), respectively. The pooled results consistently favored next-generation sequencing (NGS)- over polymerase chain reaction-based methodologies. The best ctDNA performance in terms of sensitivity, specificity, and AUC (0.85, 0.99, and 0.94, respectively) was observed in the low-time sampling subgroup (⩽18 days between tissue and plasma collection). Meta-regression and subgroup analyses highlighted sampling time as a possible major cause of heterogeneity.ConclusionsThese findings reliably estimate the high ctDNA accuracy for the detection of PIK3CA mutations. A ctDNA-first approach for the assessment of PIK3CA mutational status by NGS may accurately replace tissue tumor sampling, representing the preferable strategy at diagnosis of metastatic BC in patients who present with visceral involvement and at least two metastatic lesions, primarily given low clinical compliance or inaccessible metastatic sites.

Project description:Melanoma has the highest mortality rate among skin cancers, and early-diagnosis is essential to maximize survival rate. The current procedure for melanoma diagnosis is based on dermoscopy, i.e., a qualitative visual inspection of lesions with intrinsic limited diagnostic reliability and reproducibility. Other non-invasive diagnostic techniques may represent valuable solutions to retrieve additional objective information of a lesion. This review aims to compare the diagnostic performance of non-invasive techniques, alternative to dermoscopy, for melanoma detection in clinical settings. A systematic review of the available literature was performed using PubMed, Scopus and Google scholar databases (2010-September 2020). All human, in-vivo, non-invasive studies using techniques, alternative to dermoscopy, for melanoma diagnosis were included with no restriction on the recruited population. The reference standard was histology but dermoscopy was accepted only in case of benign lesions. Attributes of the analyzed studies were compared, and the quality was evaluated using CASP Checklist. For studies in which the investigated technique was implemented as a diagnostic tool (DTA studies), the QUADAS-2 tool was applied. For DTA studies that implemented a melanoma vs. other skin lesions classification task, a meta-analysis was performed reporting the SROC curves. Sixty-two references were included in the review, of which thirty-eight were analyzed using QUADAS-2. Study designs were: clinical trials (13), retrospective studies (10), prospective studies (8), pilot studies (10), multitiered study (1); the remain studies were proof of concept or had undefined study type. Studies were divided in categories based on the physical principle employed by each diagnostic technique. Twenty-nine out of thirty-eight DTA studies were included in the meta-analysis. Heterogeneity of studies' types, testing strategy, and diagnostic task limited the systematic comparison of the techniques. Based on the SROC curves, spectroscopy achieved the best performance in terms of sensitivity (93%, 95% CI 92.8-93.2%) and specificity (85.2%, 95%CI 84.9-85.5%), even though there was high concern regarding robustness of metrics. Reflectance-confocal-microscopy, instead, demonstrated higher robustness and a good diagnostic performance (sensitivity 88.2%, 80.3-93.1%; specificity 65.2%, 55-74.2%). Best practice recommendations were proposed to reduce bias in future DTA studies. Particular attention should be dedicated to widen the use of alternative techniques to conventional dermoscopy.

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Diagnostic Accuracy of PIK3CA Mutation Detection by Circulating Free DNA in Breast Cancer: A Meta-Analysis of Diagnostic Test Accuracy.

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