Single-Cell Resolution Mutational Profiling in Breast Cancer


DEPArray™’s imaging reports and Sanger Sequence result.

DEPArray™’s imaging reports and Sanger Sequence result.

A new study from Sidney Kimmel Cancer Center at Jefferson demonstrated the feasibility of detecting cancer-associated gene mutations in circulating tumor cells (CTC) isolated from patients — providing a powerful new tool for clinicians and cancer researchers.

Published in Clinical Cancer Research, the project was led by senior authors Paolo M. Fortina, MD, PhD, and Massimo Cristofanilli, MD, of Northwestern University, together with collaborators from SKCC directed by Karen Knudsen, PhD, Director of the Sidney Kimmel Cancer Center, and other collaborators from research institutes in Rome and Milan. The first author of the study, Carmela Paolillo, PhD, conducted the research project as an SKCC postdoctoral fellow with Dr. Fortina in the Department of Cancer Biology at Thomas Jefferson University.

The team tested whether mutations in the estrogen receptor 1 (ESR1) gene, which are linked to breast cancer, can be detected in individual CTCs from patients with metastatic breast cancer. Using state-of-the-art technology, they were able to detect ESR1 mutations and correlate them with other properties of the CTCs, such as their acquisition of endocrine resistance, clonal relationship to other tumor cells, and whether the cells might harbor additional novel and potential cancer-driving mutations.

The investigators noted that the study has immediate application to breast cancer diagnosis and treatment. “We validated a workflow for liquid biopsy that should facilitate early detection of ESR1 mutations, the emergence of endocrine resistance, and the choice of further target therapy,” they wrote. They also explained that “the technology may be useful in high-risk patients to predict recurrence,” for example, by forecasting the success of endocrine therapy in a particular patient, or the need to switch to new therapies before onset of metastatic disease.

This strategy for detecting gene mutations in single CTCs has broader implications beyond breast cancer, as it suggests that CTCs could potentially be used as biomarkers to detect and characterize genetic variants associated with many types of cancer. In this regard, the investigators pointed out that “the analysis of individual CTCs could facilitate identification of new cancer mutations and genes involved in therapeutic resistance. Given the relative ease of obtaining CTCs from patients, this method also allows for real-time molecular monitoring over the course of patient treatment, which would help guide new treatment modalities with potentially important impacts on outcome,” they said.

The team emphasized that expansion and further validation of the CTC analysis technology using larger cohorts of patients are critical next steps in the translation of these findings into more widespread clinical practice for cancer treatment.