RT Journal Article
SR Electronic
T1 DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e000230
DO 10.1136/jitc-2019-000230
VO 8
IS 1
A1 Yasser Ged
A1 Joshua L Chaim
A1 Renzo G DiNatale
A1 Andrea Knezevic
A1 Ritesh R Kotecha
A1 Maria I Carlo
A1 Chung-Han Lee
A1 Ashley Foster
A1 Darren R Feldman
A1 Min Yuen Teo
A1 Gopakumar Iyer
A1 Timothy Chan
A1 Sujata Patil
A1 Robert J Motzer
A1 A Ari Hakimi
A1 Martin H Voss
YR 2020
UL http://jitc.bmj.com/content/8/1/e000230.abstract
AB Background Loss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and relevance to I/O in metastatic clear cell RCC (ccRCC) are unknown.Methods Genomic data and treatment outcomes were retrospectively collected for patients with metastatic ccRCC. Tumor and germline DNA were subject to targeted next generation sequencing across >400 genes of interest, including 34 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR). Association between DDR status and therapeutic benefit was investigated separately for I/O and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy.Results Del DDR were detected in 43/229 patients (19%). The most frequently altered genes were CHEK2 and ATM. Clonality analysis was performed in 27 somatic DDR mutations and 17 were clonal (63%). For patients with I/O treatment, Del DDR status was associated with superior overall survival (log-rank p=0.049); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Del DDR was 0.41 (95% CI: 0.14–1.14; p=0.09). No association was seen with VEGF-TKI treatment (log-rank p=0.903).Conclusion Del DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Loss-of-function events in these genes may affect outcome with I/O therapy in metastatic RCC, and these hypothesis-generating results deserve further study.