Circulating tumour DNA dynamics for assessment of molecular residual disease and for intercepting resistance in breast cancer

Abstract

Purpose of reviewLongitudinal evaluation of circulating tumour DNA (ctDNA) represents a promising tool for monitoring tumour evolution. In patients with breast cancer, ctDNA dynamics for the assessment of molecular residual disease (MRD) and resistances may, respectively, help clinicians in treatment modulation of adjuvant treatments, and in anticipating resistance to ongoing treatments and switch treatments before clinical progression, to improve disease control. Anyway, the introduction of this dynamic biomarker into clinical practice requires the demonstration of analytical validity, clinical validity and clinical utility.Recent findingsIn early breast cancer setting, several observational studies demonstrated the clinical validity of MRD monitoring through ctDNA in identifying patients at a higher risk of relapse, but many clinical trials evaluating the clinical utility are still ongoing, and few data resulted in inconclusive results.Instead, ctDNA dynamics for intercepting resistance have not been fully evaluated in terms of clinical validity, because monitoring schedules of most observational studies are not intensive. The only trial assessing their clinical utility (PADA-1) demonstrated a benefit in terms of progression-free survival, portraying a new landscape for clinical trials in this space.SummaryRigorous clinical trials with adequate assays and patient-relevant endpoints are paramount to demonstrate the clinical utility of ctDNA dynamics and eventually increase clinical outcomes.

The Value of Tumor Infiltrating Lymphocytes (TIL) for Predicting the Response to Neoadjuvant Chemotherapy (NAC) in Breast Cancer according to the Molecular Subtypes

“…In this systematic review, in the case of HER2+ and TNBC patients, the cut-off value of sTIL was 20%, a value from which significant results were obtained regarding the tumor response rate to NAC therapy. The conclusion of another meta-analysis published by Zhao-hua Gao et al in 2020, which included 33 profile studies (18,170 patients) underlines the predictive value of sTILs regarding the tumor response rate to NAC in the case of patients with a TNBC and HER2+ molecular profile [52]. High values of sTILs are associated with a degree of favorable response to the NAC and with a longer-term survival (OS).…”

Optimizing Postneoadjuvant Treatment in Patients With Early Breast Cancer Achieving Pathologic Complete Response

“…28,29,32,33 Additionally, MRD assessed by circulating tumor DNA (ctDNA) may improve the identification and characterization of the pCR population at higher risk. 34 Indeed, once pCR is achieved, the liquid biopsy remains the only means to reassess tumor biology/resistance. Undetectable ctDNA after NACT was demonstrated to better correlate with RFS than pCR, across all BC phenotypes, and to further improve patient stratification if combined with pCR.…”

Tumor Infiltrating Lymphocytes across Breast Cancer Subtypes: Current Issues for Biomarker Assessment

“…The assessment of the clinical utility of TILs requires clinical trials with TILs as a biomarker for patient selection or patient stratification. In the case of patient selection, only patients with TILs-positive or TILs-negative disease are randomized, but analytic and clinical validity must have been robustly assessed before; in the case of patient stratification, patients with both TILs-negative and TILs-positive disease are randomized; such an approach requires four-arm randomized clinical trials with higher sample sizes, but would more strongly provide evidence of clinical utility, especially for biomarkers of uncertain significance [67,68].…”