Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.

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.

Lymphocyte to monocyte ratio-based nomogram for predicting outcomes of hepatocellular carcinoma treated with sorafenib.

BACKGROUND: The ability of the pretreatment lymphocyte to monocyte ratio (LMR) to predict outcomes of patients with hepatocellular carcinoma (HCC) receiving sorafenib is not conclusively determined. METHODS: We retrospectively studied patients treated with sorafenib for HCC in two tertiary referral centres in Asia and North America. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Predictive factors for the outcomes were determined by Cox proportional hazards models. A risk assessment tool was developed. RESULTS: Compared to the North America cohort, the Asia cohort was more heavily pretreated (72.1% vs. 35.2%; p < 0.001), had higher hepatitis B virus infection (87.6% vs. 5.6%; p < 0.001), and more distant metastases (83.2% vs. 25.4%; p < 0.001). Lower monocyte count in the Asia cohort (median 462.7 vs. 600.0/µL; p = 0.023) resulted in a higher LMR (median 2.6 vs. 1.8; p < 0.001). High LMR was associated with a significantly higher OS [hazard ratio (HR) 0.88; 95% confidence interval (CI) 0.81‒0.97; p = 0.007]. This was confirmed in a sensitivity analysis including patients treated in Asia only (HR 0.89; 95% CI 0.81‒0.97; p = 0.010). An OS nomogram was constructed with the following variables selected in the multivariate Cox model: LMR, treatment location, previous treatment, performance status, alpha-fetoprotein, lymph node metastasis, and Child‒Pugh score. The concordance score was 0.71 (95% CI, 0.67‒0.75). LMR did not predict PFS. CONCLUSION: LMR measured before sorafenib administration predicts OS in advanced HCC patients. Our OS nomogram, incorporating LMR, can be offered to clinicians to improve their ability to assess prognosis, strengthen the prognosis-based decision-making, and inform patients in the clinic.