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Enrolling by Invitation

NCT Number: NCT07372261

Validation of a Prognostic Method for Assessing the Risk of Distant Metastasis in Early-stage Breast Cancer

This is a multicenter, observational validation study designed to evaluate the prognostic performance of the PORTENT algorithm in patients with early-stage breast cancer. The model integrates clinicopathological variables and the expression levels of two small non-coding RNAs (miR-3916 and miR-3613-5p) to estimate individual risk of developing distant metastases.

The primary objective is to assess the discriminatory ability of the PORTENT algorithm for predicting distant metastasis at predefined time points after diagnosis.

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Key information

Conditions

Breast Cancer Early Stage Breast Cancer (Stage 1-3) Neoplasm Metastasis Neoplasms Neoplastic Processes Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year and older

Sex eligibility

Female

Study type

Observational

Primary location

Fondazione Casa Sollievo della Sofferenza IRCCS

San Giovanni Rotondo, FG, 71013, Italy

About this study

This multicenter retrospective observational study aims to clinically validate the PORTENT prognostic algorithm for predicting the risk of distant metastases in women with early-stage breast cancer. Female patients with Stage I-III disease from three independent cohorts with available residual tumor tissue and follow-up data will be included.

The primary endpoint of the study is the discriminatory performance of the PORTENT algorithm, assessed by the area under the receiver operating characteristic curve (AUC) for the prediction of distant metastases at 5 and 10 years from diagnosis.

The algorithm integrates established clinicopathological prognostic factors (tumor stage, histological grade, and Ki67-MIB1) with the expression levels of miR-3916 and miR-3613-5p. MicroRNA expression and target protein expression will be evaluated using RT-qPCR and immunohistochemistry.

Secondary and exploratory analyses will include model calibration assessed using calibration curves and the Integrated Calibration Index (ICI), as well as survival analyses (overall survival, progression-free survival, and metastasis-free survival) performed using Cox proportional hazards models.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Stage I-III breast cancer
  • Residual tumor tissue available
  • Written informed consent

Exclusion criteria

  • Age <18
  • Stage IV at diagnosis
  • Refusal or inability to provide informed consent

Treatment and study plan

Validation of Prognostic tool

Diagnostic Test

Collection of Clinical History: Clinical data, including medical history, clinicopathological features (e.g., age, histology, receptor and nodal status), and follow-up information (presence or absence of metastasis, patient vital status), will be collected and entered into a dedicated platform by. Follow-up updates are scheduled by Month 48 of the project (December 31, 2025) to ensure timely and accurate patient outcome data.

Laboratory Analysis: Residual tumor sections prepared by the Pathology Unit of each participating center will be sent to the Oncology Laboratory at CSS-IRCCS, where RNA will be extracted using standardized experimental procedures. Expression levels of miR-3916, miR-3613-5p, and their target genes will be analyzed by quantitative real-time PCR (RT-qPCR). Protein expression of target genes will be assessed via immunohistochemistry. Additionally, the extracted RNA will be analyzed at the Gerobiomics and Exposomics Laboratory of IRST IRCCS.

Primary outcomes

  1. Discriminatory Performance of the Prognostic Algorithm (AUC) for Prediction of Distant Metastasis Within 5 Years From Diagnosis

    Time frame: 5 years from diagnosis; interim analysis at March 2027.

    Area under the Receiver Operating Characteristic (ROC) curve (AUC) with 95% confidence intervals for patient-level risk probabilities generated by the prognostic algorithm to predict the occurrence of distant metastases within 5 years after breast cancer diagnosis. Discrimination will be assessed using ROC curve analysis and DeLong's test.

  2. Discriminatory Performance of the Prognostic Algorithm (AUC) for Prediction of Distant Metastasis Within 10 Years From Diagnosis

    Time frame: 10 years from diagnosis; final analysis after completion of 10-year follow-up for all participants (expected by 2029).

    Area under the Receiver Operating Characteristic (ROC) curve (AUC) with 95% confidence intervals for patient-level risk probabilities generated by the prognostic algorithm to predict the occurrence of distant metastases within 10 years after breast cancer diagnosis. Discrimination will be assessed using ROC curve analysis and DeLong's test.

Secondary outcomes

  1. Calibration of the Prognostic Model at 5 Years (Integrated Calibration Index)

    Time frame: 5 years from diagnosis; interim analysis at March 2027.

    Calibration of the prognostic algorithm will be evaluated at 5 years using the Integrated Calibration Index (ICI) and calibration plots to assess agreement between predicted and observed distant metastasis risk.

  2. Calibration of the Prognostic Model at 10 Years (Integrated Calibration Index)

    Time frame: 10 years from diagnosis; final analysis after completion of 10-year follow-up (expected by 2029).

    Calibration of the prognostic algorithm will be evaluated at 10 years using the Integrated Calibration Index (ICI) and calibration plots to assess agreement between predicted and observed distant metastasis risk.

  3. Difference in Discriminatory Performance Between Prognostic Models (ΔAUC) at 5 Years

    Time frame: 5 years from diagnosis; interim analysis at March 2027.

    Difference in AUC between the standard clinical prognostic model (clinicopathological variables only) and the extended model including miR-3916 and miR-3613-5p expression for prediction of distant metastases at 5 years. Statistical comparison will be performed using DeLong's test.

  4. Difference in Discriminatory Performance Between Prognostic Models (ΔAUC) at 10 Years

    Time frame: 10 years from diagnosis; final analysis after completion of 10-year follow-up (expected by 2029).

    Difference in AUC between the standard clinical prognostic model (clinicopathological variables only) and the extended model including miR-3916 and miR-3613-5p expression for prediction of distant metastases at 10 years. Statistical comparison will be performed using DeLong's test.

  5. Classification Performance of the Prognostic Algorithm at 10 Years (Sensitivity, Specificity, PPV, NPV)

    Time frame: 10 years from diagnosis; final analysis after completion of 10-year follow-up (expected by 2029).

    Estimation of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), with 95% confidence intervals, for predefined probability thresholds corresponding to low (<10%), intermediate (10-30%), and high (>30%) 10-year distant metastasis risk categories.

  6. Association Between miR-3916 and miR-3613-5p Expression and Overall Survival

    Time frame: Up to 10 years from diagnosis; final analysis after completion of follow-up (expected by 2029).

    Association between miR-3916 and miR-3613-5p expression levels and overall survival, assessed using hazard ratios and 95% confidence intervals from Cox proportional hazards models.

  7. Prognostic Algorithm Performance Within PAM50 Molecular Subgroups

    Time frame: 5 and 10 years from diagnosis; final analysis after completion of follow-up (expected by 2029).

    Discriminatory performance and calibration of the prognostic algorithm within PAM50 molecular subgroups (Luminal A, Luminal B, HER2-enriched, Basal-like), evaluated using AUC and calibration metrics.

  8. Analytical Validity of miRNA Expression Assessment

    Time frame: Data collection and analysis completed by March 2027.

    Assessment of analytical validity of miR-3916 and miR-3613-5p expression measurement, including RNA yield, RT-qPCR amplification success rate, and assay reproducibility. This outcome assesses technical performance only.

Other outcomes

  1. Identification and Analytical Validation of miRNA Target Genes

    Time frame: Data collection and analyses completed by March 2027.

    Identification and analytical validation of molecular target genes regulated by miR-3916 and/or miR-3613-5p using in silico prediction, experimental confirmation, assay development, and RT-qPCR analytical validation.

  2. Correlation of miRNA Target Gene Expression With Clinical Outcomes and Clinicopathological Features

    Time frame: Up to 10 years from diagnosis; final analysis after completion of follow-up (expected by 2029).

    Correlation of mRNA and protein expression levels of validated miRNA target genes with clinical outcomes (overall survival, progression-free survival, metastasis-free survival) and clinicopathological characteristics.

  3. Improvement in Prognostic Risk Classification (NRI and IDI)

    Time frame: 5 and 10 years from diagnosis; final analysis after completion of follow-up (expected by 2029).

    Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) assessing improvement in patient risk stratification achieved by extending the prognostic algorithm with miRNA target gene expression data.

Sponsors and collaborators

Lead sponsor

Casa Sollievo della Sofferenza IRCCS

Other

Collaborators

  • Fondazione Humanitas per la Ricerca
  • Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
  • Fondazione IRCCS Policlinico San Matteo di Pavia
  • IRCCS Centro di Riferimento Oncologico della Basilicata
  • Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale
  • Istituto Nazionale Tumori Regina Elena
  • Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS
  • Istituto Tumori Giovanni Paolo II, BARI

Registry information

Official study title

Dissecting the Role of miR-3916 and miR3613-5p in Breast Cancer and Developing a Metastases Predictor PORTENT Algorithm

Acronym: PORTENT

Important dates

Study start
2022
Primary completion
2026
Study completion
2026
First posted
Jan 28, 2026
Registry last updated
Jan 30, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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