ROLE OF MIRNA PROFILING IN PREDICTING CHEMOTHERAPY RESPONSE IN BREAST CANCER

Abstract

Objective
This randomized controlled trial evaluated whether baseline microRNA (miRNA) profiling predicted chemotherapy response among women with breast cancer treated at a tertiary care hospital in Pakistan, and whether integrating a validated miRNA signature into clinical decision-making improved pathological and radiological treatment outcomes.

Methods
Women aged 18–70 years with newly diagnosed, stage II–III, non-metastatic breast cancer who were planned for anthracycline–taxane-based neoadjuvant chemotherapy were enrolled and randomized 1:1 to an miRNA-guided arm or a standard-care arm. In both arms, plasma was collected at baseline and after two chemotherapy cycles for profiling of a predefined panel of 24 circulating miRNAs selected from prior literature (including miR-21-5p, miR-34a-5p, miR-155-5p, let-7 family members, and miR-210-3p).

 In the intervention arm, treating oncologists received a report categorizing patients as “predicted responder” or “predicted non-responder” based on a multivariable logistic model derived in an internal pilot cohort; treatment could be escalated or switched in predicted non-responders. In the control arm, clinicians were blinded to miRNA data and managed patients according to institutional protocols. The primary endpoint was pathological complete response (pCR) in breast and axilla. Key secondary endpoints were radiologic response rate, progression-free survival (PFS), and the discriminative performance (area under the receiver operating characteristic curve, AUC) of the miRNA signature for pCR and radiologic response.

Results
A total of 228 participants were randomized (miRNA-guided arm, n = 114; standard-care arm, n = 114). Baseline clinicopathologic characteristics, including age, molecular subtype, and stage, were balanced between arms. The composite 8-miRNA signature (miR-21-5p, miR-34a-5p, miR-155-5p, miR-210-3p, miR-221-3p, miR-26a-5p, miR-195-5p, and let-7d-5p) showed independent association with pCR after adjustment for subtype, grade, and Ki-67. In the overall cohort, the signature predicted pCR with an AUC of 0.79 (95 % CI 0.73–0.85) and predicted radiologic partial/complete response with an AUC of 0.76 (95 % CI 0.70–0.82). In the miRNA-guided arm, 41.2 % of patients achieved pCR compared with 27.2 % in the standard-care arm (risk difference 14.0 %, 95 % CI 3.0–25.1; p = 0.014). Predicted non-responders who underwent early regimen modification experienced higher pCR rates than historical non-responders in the control arm and had improved 2-year PFS (HR for progression or death 0.61, 95 % CI 0.40–0.94). Safety profiles and rates of grade 3–4 toxicity were comparable between arms.

Conclusion
In this tertiary Pakistani cohort, circulating miRNA profiling provided independent and clinically meaningful prediction of chemotherapy response in breast cancer and, when prospectively integrated into treatment decisions, modestly improved pCR and short-term PFS without increasing toxicity. These findings supported further validation of the 8-miRNA signature and highlighted the feasibility of incorporating liquid-biopsy–based molecular tools into routine breast cancer care in low- and middle-income settings.