Clinicogenomic Characterization of Primary Sclerosing Cholangitis-Associated Biliary Tract Cancers.
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Wang Xin, Haro-Silerio Jaime Ivan, Beaudry Felix E G, Borgida Ayelet, Abbas-Aghababazadeh Farnoosh, Sahebi Nasim Bondar, Wang Michael, Fox Daniel Aaron, Nuh Mohamd, Hsiang Monica, Bhamidipati Deepak, Kang Hyunseon Christine, Cox Veronica, Ludmir Ethan, Koay Eugene J, Kwong Lawrence, Quentin Kimana, Chatterjee Deyali, Chun Yun Shin, Cao Hop Tran, Meric-Bernstam Funda, Hu Ian, Dodd Anna, Hamza Oumaima, Hildebrand Maggie, Bucur Roxana, Hirschfield Gideon M, Vogel Arndt, O'Kane Grainne M, Gallinger Steven, Haibe-Kains Benjamin, Notta Faiyaz, Sapisochin Gonzalo, Knox Jennifer J, Javle Milind M, Lee Sunyoung S, Grant Robert C
Аннотация
EXPERIMENTAL DESIGN: This was a retrospective cohort study of patients with BTC with underlying PSC treated at MD Anderson Cancer Center (N = 46) and Princess Margaret Cancer Centre (N = 16), which were contrasted to patients with non-PSC-related BTC (N = 146). We compared outcomes between PSC and non-PSC, and PSC treated with and without immunotherapy. A combination of targeted sequencing (N = 139), whole-genome sequencing (WGS; N = 27), and WGS with paired RNA sequencing (N = 33) delineated the genomic and transcriptomic landscape of PSC-associated BTCs.
RESULTS: In PSC-related BTC, the addition of immunotherapy to chemotherapy was associated with improved first-line progression-free survival (PFS; N = 22 vs. 11; median PFS, 12.2 vs. 4.7 months; P = 0.01). Immune-related adverse events were rare (N = 2, 12.5%) and improved after treatment discontinuation. Classic actionable genomic alterations, including IDH1 mutations and FGFR2 fusions, were absent in PSC-related BTCs. PSC tumors had a 2.6-fold higher tumor mutational burden (P = 3.28e-05) compared with non-PSC tumors. Transcriptomic profiling revealed a subset of PSC tumors displaying RNA signatures of immunotherapy response.
CONCLUSIONS: Immunotherapy in PSC-associated BTCs seemed safe, with a potential signal of effectiveness. Given the sample size and retrospective design, these results are hypothesis-generating. Together, these results demonstrate the unique biology underlying PSC-associated BTCs, highlighting the need for prospective trials and the development of specialized treatment strategies.