TY - JOUR
T1 - ctDNA guiding adjuvant immunotherapy in urothelial carcinoma
AU - Powles, Thomas
AU - Assaf, Zoe June
AU - Davarpanah, Nicole
AU - Banchereau, Romain
AU - Szabados, Bernadett E.
AU - Yuen, Kobe C.
AU - Grivas, Petros
AU - Hussain, Maha
AU - Oudard, Stephane
AU - Gschwend, Jürgen E.
AU - Albers, Peter
AU - Castellano, Daniel
AU - Nishiyama, Hiroyuki
AU - Daneshmand, Siamak
AU - Sharma, Shruti
AU - Zimmermann, Bernhard G.
AU - Sethi, Himanshu
AU - Aleshin, Alexey
AU - Perdicchio, Maurizio
AU - Zhang, Jingbin
AU - Shames, David S.
AU - Degaonkar, Viraj
AU - Shen, Xiaodong
AU - Carter, Corey
AU - Bais, Carlos
AU - Bellmunt, Joaquim
AU - Mariathasan, Sanjeev
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/7/15
Y1 - 2021/7/15
N2 - 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 relapse1. 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.
AB - 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 relapse1. 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.
UR - http://www.scopus.com/inward/record.url?scp=85108144887&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03642-9
DO - 10.1038/s41586-021-03642-9
M3 - Article
C2 - 34135506
AN - SCOPUS:85108144887
SN - 0028-0836
VL - 595
SP - 432
EP - 437
JO - Nature
JF - Nature
IS - 7867
ER -