Chinese-American Scientific Team Secures Largest NCI Grant in Breast Cancer CTC Research to Decipher Circulating Tumor Cells via Single-Cell Genomic Analysis

Recently, VCBeat (WeChat ID: vcbeat) learned that the U.S. National Cancer Institute (NCI) has announced a $2.7 million funding award for a multicenter study. The five-year study aims to decipher the genetic information of circulating tumor cells (CTCs) at the single-cell level, thereby advancing the development of precision medicine for breast cancer.

This project is the largest large-scale patient population-based study funded by the NCI in the field of single-cell CTC research for breast cancer to date.

In 2011, the U.S. National Research Council proposed the concept of precision medicine, driven by deepening insights into human genetics and a growing understanding of the relationship between patients’ clinical phenotypes and their drug responses.

Precision medicine is a novel strategy for disease prevention and treatment that takes into account individual differences in genetics, environment, and lifestyle. It will help healthcare practitioners and researchers accurately predict specific diseases and play a significant role in therapeutic and preventive decision-making.

It is widely acknowledged that tumor heterogeneity contributes to variations in individual treatment outcomes. In the era of precision medicine, leveraging patients’ genetic information to select the most targeted and optimal therapeutic regimen has long been a persistent goal for clinicians.

Traditional tumor tissue biopsy can provide valuable genetic information, but its invasive nature prevents its repeated use during long-term follow-up of cancer patients. Furthermore, tumor tissue samples only offer a snapshot of genetic information at a specific site and time point, failing to monitor tumor evolution in real time or guide the timely adjustment of clinical treatment regimens.

In recent years, liquid biopsy technologies leveraging circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have emerged, overcoming the limitations of tissue biopsy and rightfully becoming the cornerstone of precision medicine.

Breast cancer patients may experience local recurrence, distant metastasis, or even death during treatment and follow-up.

An article published in The New England Journal of Medicine in 2004 demonstrated that the detection of a high number of circulating tumor cells (CTCs) in patients’ blood can independently predict poor progression and adverse survival outcomes in metastatic breast cancer.

Following the FDA’s approval of the CellSearch system for clinical use in circulating tumor cell (CTC) enumeration, numerous studies have further affirmed the prognostic value of CTC detection in breast cancer and other malignancies. However, results from the large-scale Phase III randomized controlled trial SWOG S0500, published in 2014, demonstrated that adjusting clinical treatment regimens solely based on changes in CTC counts did not significantly improve overall survival in patients with metastatic breast cancer.

Therefore, CTC-based detection requires the analysis of patients' tumor information at the single-cell level to achieve the goal of precision medicine. Single-cell CTC detection has also become a focal point and priority in contemporary oncology research.

According to VCBeat, the project plans to recruit 300 patients with metastatic breast cancer and 200 patients with non-metastatic breast cancer for a five-year follow-up study. Researchers will regularly collect peripheral blood from each patient, isolate circulating tumor cells (CTCs) for single-cell sequencing, and monitor and analyze treatment responses and prognosis in breast cancer patients.

The project is led by Professor Huashan Yang of the Sidney Kimmel Cancer Center at Thomas Jefferson University in the United States. He introduced to VCBeat that this study will integrate two existing technologies: the FDA-approved CellSearch system and the DEPArray system for single-cell isolation.

Following CTC enrichment and isolation, researchers will employ novel sequencing and analytical methods for single-cell CTC analysis. By comparing the trends in genetic variations of CTCs between baseline and treatment follow-up periods, they aim to further elucidate the precise relationship between tumor evolution and therapeutic response.

To achieve this objective, researchers will employ a novel statistical genetics algorithm to conduct comprehensive big data analysis of CTC genetic variations. The study will establish a statistical model based on Bayesian algorithms to significantly enhance the accuracy and reliability of single-cell mutation analysis in CTCs.

The algorithm employed in this project is also applicable to single-cell genetic analysis of circulating tumor cells (CTCs) in other solid tumors. Therefore, the findings of this study can also serve as a reference for research on other solid tumors.

According to Professor Yang, the study will also collect and analyze ctDNA data from each sample, integrating CTCs and ctDNA—the two primary tools of liquid biopsy—for comprehensive analysis, thereby maximizing the clinical utility of liquid biopsy in therapeutic applications.

This project is a multicenter collaborative research study.

Professor Hu Shan Yang, the project leader, is affiliated with the Department of Medical Oncology at the Sidney Kimmel Cancer Center, Thomas Jefferson University, and concurrently serves as the Director of the Laboratory for Circulating Tumor Cells. For many years, Professor Yang has been dedicated to cancer risk prediction and prognostic assessment, and he is an expert in the fields of cancer genetics and epidemiology.

In addition, there are two other important collaborators: Professor Li Bingshan from the Vanderbilt Institute for Genetics and Genomics at Vanderbilt University, and Professor Massimo Cristofanilli from the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

Professor Li focuses his research on statistical genetics and next-generation sequencing algorithms. VCBeat has previously reported on iDriver, a precision oncology decision-support tool developed by him. iDriver is a tool based on the integrated analysis of medical big data, and the related paper was earlier published in the prestigious journal Bioinformatics.

Professor Li recently secured a large U01 grant from the National Human Genome Research Institute (NHGRI) to lead data analysis for the NHGRI’s Genome Sequencing Project (GSP). Supported by the NIH, the GSP is currently the largest whole-genome sequencing project worldwide, conducting deep sequencing on 200,000 individuals to study seven common complex diseases.

Professor Cristofanilli is a world pioneer in the field of circulating tumor cell (CTC) research in breast cancer. He was the first to propose, in the New England Journal of Medicine, the criterion of “≥5 CTCs per 7.5 mL of peripheral blood” as a threshold for poor prognosis in patients with metastatic breast cancer. This cutoff value remains widely adopted by oncology researchers and clinicians alike. Furthermore, this pivotal study directly led to the U.S. Food and Drug Administration’s (FDA) approval of the CellSearch system for CTC enumeration as a prognostic tool in metastatic breast cancer.

A robust team with interdisciplinary, multi-domain collaboration is the guarantee of this study's success.

Liquid biopsy circumvents the challenges associated with tissue biopsy, such as sample acquisition difficulties and invasiveness, enabling real-time, dynamic, and high-frequency monitoring of patients. In recent years, rapid advancements have been made in research on early cancer screening and post-treatment prognosis, demonstrating broad application prospects and significant market potential.

However, several challenges in CTC liquid biopsy remain to be overcome, including sample heterogeneity, amplification errors, mutation specificity, background noise and biological signals, multidimensional data integration, and big data mining. The expected outcomes of this study will help address these issues to some extent.

“Although the data generated in the study are not currently used directly in clinical practice to guide the treatment of participants in this study,” Professor Yang pointed out, “the results of this study will ultimately have a significant impact on CTC liquid biopsy and the precision treatment of breast cancer.”