Cellular Residual Disease (CRD) in Early Breast Cancer -Expanding the Concept of Minimal Residual Disease Monitoring?

Overview

Journal J Liq Biopsy

Date 2025 Mar 3

PMID 40026561

Authors

Mara S Serafini

Elisabetta Molteni

Eleonora Nicolo

Lorenzo Gerratana

Carolina Reduzzi

Massimo Cristofanilli

Affiliations

Soon will be listed here.

Abstract

Despite a significant evolution in treatment strategies for early breast cancer (EBC) patients, up to 30% of them experience recurrence due to occult micrometastasis. The minimal residual disease (minimal RD) in EBC patients after the treatment with curative intent cannot be easily detected by clinical examination and radiological imaging, as they are both burdened by limited sensitivity. A new frontier and promising approach to address this unmet need is the study of liquid biopsy (LB). The most studied tumor-derived analytes in the peripheral blood for minimal RD monitoring are currently: i) the circulating tumor DNA (ctDNA), for the detection of somatic DNA alterations, so referred to as molecular residual disease (MRD); ii) circulating tumor cells (CTCs), for the detection of cellular residual disease (CRD). MRD detection, while reaching a high specificity, is still presenting a number of limitations. On the other hand, CRD allows a real-time disease monitoring, detecting live cells, and possess the potential to provide an enormous amount of biological information. Indeed, CTCs can provide a multi-level portrait (, DNA, RNA and proteins) of the tumor, longitudinally depicting its evolving landscape, and can be used for functional () characterization. Moreover, CRD goes beyond the association with the risk of recurrence: predictive biomarkers for treatment response can also be evaluated. Nevertheless, CTCs are less studied in this context, because of their need to be immediately processed and their limited detection in a small fraction of patients in the early and post-surgery setting. These limitations could however be overcome by the use of newly developed technologies that enable an increased CTC detection rate and retrospective studies. Here, we review the strengths and limitations of using MRD and CRD for minimal RD detection, focusing on the methodologies available for LB analysis in this setting, and on the main clinical studies investigating MRD and CRD in EBC. Considering the limits and the advantages of both MRD and CRD, we propose the integration of ctDNA and CTCs as complementary tools for minimal RD assessment to achieve a synergistic and novel approach for minimal RD analysis.

References

Stergiopoulou D, Markou A, Strati A, Zavridou M, Tzanikou E, Mastoraki S . Comprehensive liquid biopsy analysis as a tool for the early detection of minimal residual disease in breast cancer. Sci Rep. 2023; 13(1):1258. PMC: 9870904. DOI: 10.1038/s41598-022-25400-1. View

Chen H, Zhou Q . Detecting liquid remnants of solid tumors treated with curative intent: Circulating tumor DNA as a biomarker of minimal residual disease (Review). Oncol Rep. 2023; 49(5). PMC: 10152452. DOI: 10.3892/or.2023.8543. View

Sparano J, ONeill A, Alpaugh K, Wolff A, Northfelt D, Dang C . Association of Circulating Tumor Cells With Late Recurrence of Estrogen Receptor-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2018; 4(12):1700-1706. PMC: 6385891. DOI: 10.1001/jamaoncol.2018.2574. View

Radovich M, Jiang G, Hancock B, Chitambar C, Nanda R, Falkson C . Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial. JAMA Oncol. 2020; 6(9):1410-1415. PMC: 7349081. DOI: 10.1001/jamaoncol.2020.2295. View

Newman A, Bratman S, To J, Wynne J, Eclov N, Modlin L . An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014; 20(5):548-54. PMC: 4016134. DOI: 10.1038/nm.3519. View

Goodman C, Seagle B, Friedl T, Rack B, Lato K, Fink V . Association of Circulating Tumor Cell Status With Benefit of Radiotherapy and Survival in Early-Stage Breast Cancer. JAMA Oncol. 2018; 4(8):e180163. PMC: 6143053. DOI: 10.1001/jamaoncol.2018.0163. View

Garcia-Murillas I, Chopra N, Comino-Mendez I, Beaney M, Tovey H, Cutts R . Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer. JAMA Oncol. 2019; 5(10):1473-1478. PMC: 6681568. DOI: 10.1001/jamaoncol.2019.1838. View

Fernandez-Santiago C, Lopez-Lopez R, Pineiro R . Models to study CTCs and CTC culture methods. Int Rev Cell Mol Biol. 2023; 381:57-98. DOI: 10.1016/bs.ircmb.2023.07.007. View

Zhu Z, Hu E, Shen H, Tan J, Zeng S . The functional and clinical roles of liquid biopsy in patient-derived models. J Hematol Oncol. 2023; 16(1):36. PMC: 10082989. DOI: 10.1186/s13045-023-01433-5. View

10.

Vasseur A, Kiavue N, Bidard F, Pierga J, Cabel L . Clinical utility of circulating tumor cells: an update. Mol Oncol. 2020; 15(6):1647-1666. PMC: 8169442. DOI: 10.1002/1878-0261.12869. View

11.

van Dalum G, van der Stam G, Tibbe A, Franken B, Mastboom W, Vermes I . Circulating tumor cells before and during follow-up after breast cancer surgery. Int J Oncol. 2014; 46(1):407-13. DOI: 10.3892/ijo.2014.2694. View

12.

Cristofanilli M, Budd G, Ellis M, Stopeck A, Matera J, Miller M . Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004; 351(8):781-91. DOI: 10.1056/NEJMoa040766. View

13.

Aceto N, Bardia A, Miyamoto D, Donaldson M, Wittner B, Spencer J . Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158(5):1110-1122. PMC: 4149753. DOI: 10.1016/j.cell.2014.07.013. View

14.

Tachtsidis A, McInnes L, Jacobsen N, Thompson E, Saunders C . Minimal residual disease in breast cancer: an overview of circulating and disseminated tumour cells. Clin Exp Metastasis. 2016; 33(6):521-50. PMC: 4947105. DOI: 10.1007/s10585-016-9796-8. View

15.

Barradas A, Terstappen L . Towards the Biological Understanding of CTC: Capture Technologies, Definitions and Potential to Create Metastasis. Cancers (Basel). 2013; 5(4):1619-42. PMC: 3875957. DOI: 10.3390/cancers5041619. View

16.

Sharma S, Zhuang R, Long M, Pavlovic M, Kang Y, Ilyas A . Circulating tumor cell isolation, culture, and downstream molecular analysis. Biotechnol Adv. 2018; 36(4):1063-1078. PMC: 5971144. DOI: 10.1016/j.biotechadv.2018.03.007. View

17.

Krol I, Schwab F, Carbone R, Ritter M, Picocci S, De Marni M . Detection of clustered circulating tumour cells in early breast cancer. Br J Cancer. 2021; 125(1):23-27. PMC: 8257701. DOI: 10.1038/s41416-021-01327-8. View

18.

Larribere L, Martens U . Advantages and Challenges of Using ctDNA NGS to Assess the Presence of Minimal Residual Disease (MRD) in Solid Tumors. Cancers (Basel). 2021; 13(22). PMC: 8616165. DOI: 10.3390/cancers13225698. View

19.

Zhou Y, Zhou J, Hao X, Shi H, Li X, Wang A . Efficacy relevance of PD-L1 expression on circulating tumor cells in metastatic breast cancer patients treated with anti-PD-1 immunotherapy. Breast Cancer Res Treat. 2023; 200(2):281-291. DOI: 10.1007/s10549-023-06972-6. View

20.

Turner N, Swift C, Jenkins B, Kilburn L, Coakley M, Beaney M . Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer. Ann Oncol. 2022; 34(2):200-211. DOI: 10.1016/j.annonc.2022.11.005. View