Circulating tumor DNA-based predictive biomarkers in breast cancer clinical trials: a narrative review

Abstract

Breast carcinoma is the most frequent and the second leading cause of cancer mortality in women worldwide. Current treatment decisions are based on tumor profiling of the initial tissue biopsy.Cancer though evolves both spatially and temporarily in a significant percentage of patients during treatment. However, sequential biopsies from the primary tumor or its metastatic sites are not either convenient or feasible in the majority of cases. In the era of precision medicine, analysis of circulating bloodbased biomarkers in the field of liquid biopsies provides an insight into the dynamic molecular profiling of the primary tumor and its metastases, in a relatively non-invasive way. The latter permits not only patient stratification but also longitudinal evaluation of treatment response, when incorporated into clinical trials. This review summarizes the results from recent and ongoing circulating tumor DNA (ctDNA)based biomarker-driven clinical trials, with respect to ctDNA analysis' predictive role, both in adjuvant, neo-adjuvant, and metastatic setting. Furthermore, current challenges in ctDNA analysis applications are critically discussed, including pre-analytical and analytical issues, and future perspectives in this field, through the conduct of well-designed, multicenter, randomized, large-scale, biomarker-stratified trials, with robust statistical methods. Despite in its infancy, ctDNA analysis holds great promise as a minimally invasive tool regarding tailored, personalized treatment guidance for breast cancer patients.

Tumor Suppressive Circular RNA-102450: Development of a Novel Diagnostic Procedure for Lymph Node Metastasis from Oral Cancer

“…LB of body fluids is commonly used for the diagnosis of multiple human diseases [36,37]. Although miRNAs have been widely assessed as biomarkers in body fluids [38,39], it was recently reported that circRNAs are highly resistant to RNA degradation by exonucleases compared with miRNAs [4,9,10].…”

Liquid Biopsy: A New Tool for Overcoming CDKi Resistance Mechanisms in Luminal Metastatic Breast Cancer

“…Therefore, changes in the molecular profiles of primary tumours and metastasis can be longitudinally studied via a non-invasive and real-time approach [ 53 ]. Various trials have demonstrated the benefits of combined CDK4/6 inhibitors plus endocrine therapy in HR+/HER2− mBC, such as increasing the PFS, regardless of menopausal status, prior therapies, endocrine sensitivity, and the site of metastasis [ 23 , 60 ]. However, certain limitations remain to be resolved, such as the lack of predictive biomarkers with which to select patients or detect resistance [ 24 ]; these are among the current topics in the context of luminal metastatic breast cancer.…”

“…The preliminary results show that ESR1 mutations were uncommon in patients that were not treated with AI in the neoadjuvant setting. In addition, a one-month treatment with palbociclib and AI decreased the ESR1 mutation rate [ 60 , 61 ].…”

Liquid Biopsy: New Tool to Overcome CDKi Resistance Mechanism in Luminal Metastatic Breast Cancer

“…Liquid biopsy provides an insight into the dynamic molecular profile of the primary tumour and its metastasis in a non-invasive and real-time approach [54]. A great variety of trials have demonstrated the benefits of combined CDK4/6 inhibitors plus endocrine therapy in HR+/HER2-MBC, such as increasing PFS regardless of menopausal status, prior therapies, endocrine sensitivity and type of metastasis [24], [57]. However, certain limitations were not resolved such as lack of predictive biomarkers to select patients or to detect resistance [25] and is one of the current topics in the context of luminal metastatic breast cancer.…”

“…As preliminary results, ESR1 mutations were uncommon in patients no-treated with AI in the neoadjuvant setting. Besides, one-month treatment with palbociclib and AI decreases ESR1 mutation rate [57], [58].…”