TY - JOUR
T1 - Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma
AU - Haber, Philipp K.
AU - Castet, Florian
AU - Torres-Martin, Miguel
AU - Andreu-Oller, Carmen
AU - Puigvehí, Marc
AU - Miho, Maeda
AU - Radu, Pompilia
AU - Dufour, Jean Francois
AU - Verslype, Chris
AU - Zimpel, Carolin
AU - Marquardt, Jens U.
AU - Galle, Peter R.
AU - Vogel, Arndt
AU - Bathon, Melanie
AU - Meyer, Tim
AU - Labgaa, Ismail
AU - Digklia, Antonia
AU - Roberts, Lewis R.
AU - Mohamed Ali, Mohamed A.
AU - Mínguez, Beatriz
AU - Citterio, Davide
AU - Mazzaferro, Vincenzo
AU - Finkelmeier, Fabian
AU - Trojan, Jörg
AU - Özdirik, Burcin
AU - Müller, Tobias
AU - Schmelzle, Moritz
AU - Bejjani, Anthony
AU - Sung, Max W.
AU - Schwartz, Myron E.
AU - Finn, Richard S.
AU - Thung, Swan
AU - Villanueva, Augusto
AU - Sia, Daniela
AU - Llovet, Josep M.
N1 - Publisher Copyright:
© 2023 AGA Institute
PY - 2023/1
Y1 - 2023/1
N2 - Background & Aims: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. Methods: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. Results: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II–related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. Conclusion: Interferon signaling and major histocompatibility complex–related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.
AB - Background & Aims: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. Methods: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. Results: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II–related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. Conclusion: Interferon signaling and major histocompatibility complex–related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.
UR - http://www.scopus.com/inward/record.url?scp=85142162479&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2022.09.005
DO - 10.1053/j.gastro.2022.09.005
M3 - Journal articles
C2 - 36108710
AN - SCOPUS:85142162479
SN - 0016-5085
VL - 164
SP - 72-88.e18
JO - Gastroenterology
JF - Gastroenterology
IS - 1
ER -