In a large, observational SCRUM-Japan GOZILA study, after a median follow-up of 11 months, patients with metastatic gastrointestinal cancers who received biomarker-matched therapies based on circulating tumour DNA (ctDNA) profiling showed a greater clinical benefit than those receiving unmatched therapy.
These findings underscore the value of ctDNA genotyping as an important tool for biomarker identification in precision oncology according to Prof. Takayuki Yoshino of the Department of Gastrointestinal Oncology, National Cancer Center Hospital East in Kashiwa, and Kindai University Faculty of Medicine in Osakasayama, Japan, and colleagues who published the findings on 16 September 2024 in the Nature Medicine.
The authors wrote in the background that despite its minimally invasive nature and rapid turnaround time, ctDNA genotyping is still not universally adopted and is often used as an alternative to tissue-based testing. Another, less-studied advantage of ctDNA analysis with similar potential to improve the quality of precision oncology care is its ability to capture heterogeneity within tumours.
The GOZILA study is a large, nationwide, prospective observational study designed to profile ctDNA genomic alterations for patients with advanced solid tumours in which patients are treated based on identified biomarkers in affiliated clinical trials or clinical practice. The GOZILA study previously showed the superiority of ctDNA genotyping in patient screening for clinical trials versus tissue genotyping.
In the latest report, the study team evaluated the efficacy of targeted therapies matched to biomarkers detected by ctDNA in patients with advanced gastrointestinal cancers and used this dataset to define the influence of biomarker clonality on outcomes in response to genomically targeted therapy.
Of the 5280 patients enrolled in the GOZILA study from January 2018 to August 2022, a total of 4037 underwent subsequent systemic therapy after blood sampling and were included in this analysis. Median age was 64 years (range, 20 to 91) with 39% of the patients being female. Major cancer types included colorectal (45%), pancreatic (22%), oesophageal (9%), gastric (8%) and biliary tract cancer (7%). The most common metastatic sites were liver (52%), lymph node (37%), lung (31%) and peritoneum (24%).
The authors commented that this large-scale cohort serves as a robust representation of patients commonly diagnosed with advanced solid tumours. This updated analysis of 4037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumours, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy.
In addition to increasing the proportion of patients receiving targeted therapy, ctDNA-directed therapy in GOZILA also demonstrated widespread efficacy, with patients more than twice as likely to respond to matched therapy and a concomitant reduction in their risk of death by more than 40% regardless of confounding baseline characteristics. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival (OS) compared with those receiving unmatched therapy with an hazard ratio of 0.54.
Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumour heterogeneity for precision oncology treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance understanding beyond the initial enrolment benefits.
One observation of particular importance in this report is that the survival advantage associated with ctDNA-guided therapy diminishes after first-line treatment. This is compatible with commonly held theories of cancer evolution under therapeutic selective pressure, which have progressively shifted targeted therapy application to earlier lines of treatment to improve survival.
The findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumours. Future studies involving a broader spectrum of cancer types are needed to validate the efficacy of ctDNA-guided therapy across diverse oncological conditions.
This work was supported by grants from the Japanese National Cancer Center Research and Development Fund, the Japan Agency for Medical Research and Development and SCRUM-Japan Funds.
Reference
Nakamura Y, Ozaki H, Ueno M, et al. Targeted therapy guided by circulating tumor DNA analysis in advanced gastrointestinal tumors. Nature Medicine; Published online 16 September 2024. DOI: https://doi.org/10.1038/s41591-024-03244-8