Abstract

Background: The “French Medicine Genomic program 2025” is an academic research program that allows to perform whole-genome/exome/RNA sequencing in advanced cancer refractory to systemic treatments to give access to off-labeled therapies adapted to genomic alterations in clinical practice. We reported results in intermediate and advanced hepatocellular carcinoma (HCC) and hepato-cholangiocarcinoma (H-CCK).

Methods: In one center, all patients with HCC or H-CCK who progressed under or did not respond to Atezolizumab/Bevacizumab with available tumor frozen samples benefited from whole-genome/exome and RNA sequencing. Targeted therapies were matched to the genomic alterations following recommendation of a molecular tumor board. Subsequent radiological response and overall survival were assessed.

Results: Between September 2020 and January 2023, among 135 patients with primary liver cancer treated by Atezolizumab/Bevacizumab, twenty patients benefited from genomic analysis after progression (16 HCC; 4 H-CCK). 19 patients had analyzable data, 70% were male, median age was 57 years, 65% had metastatic disease and 45% had vascular invasion.
The main driver genes altered in these 19 HCC/HCC-K were TP53 (47%), RB1 (37%), TERT promoter (32%), PTEN (21%), CCND1/FGF19 amplification (21%), CTNNB1 (16%), ARID1A (16%), PIK3CA (16%), ALB (16%), CDKN2A (11%) and TSC1 (11%). Mutational signatures of exposure to aflatoxin B1 were identified in 5 patients and of aristolochic acid in1 patient. A high homologous recombination score (defined by a score > 42) in 1 patient. One constitutional variant in TMEM127 predisposing to pheochromocytoma triggered family screening

Among these 19 patients, 14 patients (76%) harbored at least one actionable genomic alteration among whom 9/14 received an adapted targeted therapy (45%). One patient with H-CCK showing CDK4 amplification was treated by Palbociclib, he experienced a partial radiological response during 16 months. Another patient with H-CCK and high HER2 overexpression and a high homologous recombination score was treated by Trastuzumab/Olaparib with had a stable disease at the first imaging evaluation. One patient with an HCC and biallelic inactivation of TSC2 silencing its gene expression, harbored a complete radiological response under Everolimus. The remaining six treated patients (6 HCC) harbored a progressive disease including three patients treated by Trametinib, two by Everolimus and one by Olaparib.

Conclusion: Molecular based guided therapy is feasible in patients with HCC and H-CCK and progressing under atezolizumab/bevacizumab. Forty-five percent received a therapy adapted to a genomic alteration with a clinical benefit in one third of them.