Getting More from CTC: Advancing Clinical Precision Applications in Oncology

As one of the three pillars of liquid biopsy, circulating tumor cells (CTCs) have sparked a research frenzy in both clinical and scientific fields. However, challenges such as their scarcity, difficulty in isolation, and poor detection reproducibility have consistently hindered the application of CTC-related technologies. In late 2016, Johnson & Johnson, a key player in the CTC field, sold all assets and businesses related to its CellSearch CTC system, casting further shadow over the future prospects of CTC applications.

Nevertheless, the comprehensive tumor biological information and physiological activity possessed by circulating tumor cells (CTCs) remain irreplaceable in clinical practice. Therefore, with the emergence of next-generation detection technologies, clinical attention has once again turned to CTCs. At the 2019 Greater Bay Area Precision Oncology Forum and the 13th “CSCO-Southern” Forum on Tumor Biotherapy and Molecular Targeted Therapy, President Luo Rongcheng of Fuda Cancer Hospital presided over the sub-forum on “Clinical Precision Applications of Circulating Tumor Cells.” Participating experts engaged in lively discussions regarding the potential applications of CTCs in precision diagnosis, precision chemotherapy, and immunotherapy.

Professor Guo Shiwei from Changhai Hospital Affiliated to the Second Military Medical University shared his insights on the application of neoadjuvant therapy and novel companion diagnostics in clinical practice and research. The five-year survival rate after conventional surgical resection is less than 20%. While the widespread use of adjuvant and neoadjuvant therapies has effectively improved post-resection survival rates, it has also imposed new requirements on diagnostic techniques and information. Circulating tumor cells (CTCs) can reflect tumor heterogeneity and constitute part of the tumor microenvironment, providing early indications of micrometastasis and playing a significant role in the clinical management of pancreatic tumors. Based on novel microfluidic technology, fully viable CTCs can provide clinicians with additional information, including CTC size, roundness, nuclear-to-cytoplasmic ratio, and the association between CTC composition and tumor staging. The rich information carried by CTCs can also support clinicians in selecting more sensitive neoadjuvant regimens and facilitate exploration of the correlation between CTC PD-L1 expression and the efficacy of immune checkpoint inhibitors.

“As surgeons, we now need to leverage new technologies to gain a more comprehensive and accurate understanding of the individualized characteristics of patients’ tumors, thereby providing reliable assistance for clinical treatment and truly benefiting patients,” said Professor Guo.

Professor Xu Meng from the First Affiliated Hospital of Jinan University shared his insights on how chemotherapy can be individualized and precisely tailored in the era of precision medicine. The "Opinions of the State Council on Implementing the Healthy China Action," issued by the government in July 2019, explicitly stated that the overall five-year survival rate for cancer should reach no less than 46.6% by 2030. Comprehensive cancer treatment has become the mainstream trend in clinical practice, significantly improving survival prognosis, with chemotherapy playing a pivotal role. Furthermore, real-world cancer treatment decision-making and whole-course management are closely linked to the acquisition of more precise patient physiological information. Due to the significant inter-individual variability in response to chemotherapy, leveraging chemosensitivity testing to designate individualized chemotherapy regimens is an essential pathway to enhancing the efficacy of clinical oncology treatment. The earlier "Chemosensitivity Testing 1.0" era was based on conventional two-dimensional culture of tumor cells for anticancer drug sensitivity assessment; the "Chemosensitivity Testing 2.0" era utilized three-dimensional tumor cell culture for such assessments; while the current "Chemosensitivity Testing 3.0" era achieves precision chemotherapy based on circulating tumor cells (CTCs). This approach fully reflects tumor heterogeneity, eliminates interference from stromal cells, and features a shorter detection cycle, thereby better meeting the clinical need to capture the therapeutic time window.

“The integration of precision oncology with cancer treatment can enhance the efficacy of chemotherapy. Furthermore, leveraging key chemotherapeutic research technologies such as CTC-based drug sensitivity testing can further advance and accelerate drug development and clinical application. We should continue to encourage innovative translational research in clinical settings, guiding and adapting clinical practice through rigorous clinical data and evidence-based standards,” said Professor Xu Meng.

Director Wang Zhidong from the Eighth People’s Hospital of Changsha shared his insights on the application of immunotherapy in lung cancer. Statistics show that in 2017, both the incidence and mortality rates of lung cancer in China ranked among the highest across all tumor types. In recent years, the rapidly emerging field of immunotherapy has fundamentally reshaped the landscape of clinical guidelines for lung cancer, thereby imposing new requirements for precise clinical testing. Although various biomarkers are currently available to predict the efficacy of tumor immunotherapy, most serve as associative factors rather than causal ones.

Direct assessment of PD-1/PD-L1 may be more effective for immune checkpoint inhibitor therapy, but it requires further data support. Blind trials without testing carry the risks of increased medical costs and immune-related adverse events. In addition to indirect detection methods such as tumor mutational burden (TMB), microsatellite instability (MSI), and genetic testing for genes positively or negatively correlated with therapeutic efficacy, PD-L1 detection using circulating tumor cells (CTCs) holds significant potential. The current trend of combining immunotherapy with other treatments further necessitates a more comprehensive and accurate individual patient assessment using biomarkers that carry complete tumor information, such as CTCs. Dr. Wang Zhidong also shared clinical cases in which the treatment regimen of immune checkpoint inhibitors combined with chemotherapy was precisely optimized through CTC drug sensitivity testing and CTC-based PD-L1 detection.

“Those whose learning does not span the ages, whose insight fails to comprehend the interplay between humanity and nature, whose talent falls short of the transcendent, and whose heart lacks the compassion of a Buddha must never practice medicine, lest they mislead the world.” This passage from the Preface to Yan Yi by Pei Yizhong of the Ming Dynasty thoroughly articulates the requisite competencies and ethical values for physicians. In response to patients’ urgent needs, we must seize every precious therapeutic opportunity. Once rigorous clinical trials have demonstrated the efficacy of immunotherapy, clinicians should have the courage and responsibility to prioritize its use, thereby honoring the trust patients place in us,” stated Director Wang Zhidong.

Director Lin Rongbo from Fujian Provincial Cancer Hospital shared the most cutting-edge research findings on immunotherapy in advanced gastric cancer. At this year’s ASCO meeting, KEYNOTE-062 compared the efficacy of chemotherapy versus PD-1 immune checkpoint inhibitors in advanced gastric cancer. Immune checkpoint inhibitors significantly improved overall survival (OS) in patients with PD-L1 Combined Positive Score (CPS) >10 (median: 10.8 months vs. 17.4 months). However, the combination of immune checkpoint inhibitors and chemotherapy did not significantly improve OS compared to chemotherapy alone (median: 11.1 months vs. 12.5 months), a finding that differs from results observed in similarly designed clinical trials in head and neck cancers. Similar results were seen in KEYNOTE-181 and KEYNOTE-061, where monotherapy with immune checkpoint inhibitors demonstrated better efficacy in patients with PD-L1 CPS >10. Currently, for symptomatic patients with advanced gastric cancer, chemotherapy is still used first to alleviate symptoms, followed by consideration of immune checkpoint inhibitors based on PD-L1 CPS results. Clinicians and researchers currently hypothesize that the impact of combining chemotherapy with immune checkpoint inhibitors on the immune system may vary across different cancer types, leading to significant differences in therapeutic efficacy. Therefore, further optimization is needed regarding combination or sequential administration strategies and the sequence of treatment. On another note, numerous biomarkers are available for immune checkpoint inhibitors in gastric cancer, including TMB, TILs, MSI, EBV, and CTCs. How to accurately stratify patients requires deeper exploration by clinicians.

“Patients with highly aggressive tumors generally have shorter overall survival times and more numerous symptoms. Choosing therapies with higher short-term efficacy to improve patients’ short-term quality of life may ultimately yield better long-term overall outcomes. At times, breadth may be more important than length. Clinicians must have both the conditions and the capability to make comprehensive judgments by integrating patients’ actual clinical situations and laboratory test indicators,” stated Director Lin Rongbo.