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ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.
- Source :
-
Nature [Nature] 2021 Jul; Vol. 595 (7867), pp. 432-437. Date of Electronic Publication: 2021 Jun 16. - Publication Year :
- 2021
-
Abstract
- Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse <superscript>1</superscript> . We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFβ signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.<br /> (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Biomarkers, Tumor blood
Biomarkers, Tumor genetics
Circulating Tumor DNA genetics
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Neoplasm Recurrence, Local blood
Neoplasm Recurrence, Local genetics
Postoperative Care
Prognosis
Recurrence
Survival Analysis
Urinary Bladder Neoplasms genetics
Urinary Bladder Neoplasms immunology
Adjuvants, Pharmaceutic therapeutic use
Antibodies, Monoclonal, Humanized therapeutic use
Circulating Tumor DNA blood
Immunotherapy
Urinary Bladder Neoplasms diagnosis
Urinary Bladder Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 595
- Issue :
- 7867
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 34135506
- Full Text :
- https://doi.org/10.1038/s41586-021-03642-9