FGFR genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with FGFR GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown.Patients with CCA with FGFR GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with FGFR wild-type counterparts. Data reviewed included demographic, treatment, overall survival (OS), and GA data. Fisher's exact test, Kaplan-Meier plots, and log-rank tests were used for statistical analysis.Three hundred seventy-seven patients with CCA were identified, and 95 had FGFR GAs. FGFR2 GA was most common (n = 74, with 63 fusions) and seen in intrahepatic CCA. In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001), presented at an earlier stage (TNM stage I/II v III/IV: 35.8% v 22%, respectively; P = .001), and were associated with a longer OS compared with patients without FGFR GAs (37 v 20 months, respectively; P < .001). This difference remained significant after excluding 36 patients treated with FGFR inhibitors. There was no OS difference (P = .60) between CCA with FGFR2 fusions (n = 63) versus other FGFR GAs (n = 29). Patients with FGFR GAs had a better OS with FGFR-targeted therapy compared with standard treatment (P = .01). BAP1 mutation was the most common coexisting mutation without prognostic impact, whereas TP53 (P = .04) and CDKN2A/B (P = .04) were correlated with a shorter OS.CCA with FGFR GAs represents a unique subtype occurring in younger patients with an indolent disease course. FGFR-targeted therapy may have a positive impact on OS in this subgroup.
Antiangiogenic therapy is commonly used for the treatment of colorectal cancer (CRC). Although patients derive some clinical benefit, treatment resistance inevitably occurs. The MET signaling pathway has been proposed to be a major contributor of resistance to antiangiogenic therapy. MET is upregulated in response to vascular endothelial growth factor pathway inhibition and plays an essential role in tumorigenesis and progression of tumors. In this study, we set out to determine the efficacy of cabozantinib in a preclinical CRC patient-derived tumor xenograft model. We demonstrate potent inhibitory effects on tumor growth in 80% of tumors treated. The greatest antitumor effects were observed in tumors that possess a mutation in the PIK3CA gene. The underlying antitumor mechanisms of cabozantinib consisted of inhibition of angiogenesis and Akt activation and significantly decreased expression of genes involved in the PI3K pathway. These findings support further evaluation of cabozantinib in patients with CRC. PIK3CA mutation as a predictive biomarker of sensitivity is intriguing and warrants further elucidation. A clinical trial of cabozantinib in refractory metastatic CRC is being activated.
192 Background: An exploratory analysis of a randomized phase II study in HCC comparing doxorubicin (D) alone to doxorubicin plus sorafenib (D+S) showed a significant improvement in overall survival favoring D+S (JAMA, 2011). The results appeared promising compared to the historic outcomes seen in the pivotal sorafenib (S) trials. CALGB 80802 was designed to determine if D+S improved survival compared to S alone. Methods: Patients with histologically proven advanced HCC, no prior systemic therapy and Child-Pugh A were randomized to receive D 60 mg/m 2 every 21 days plus S 400 mg PO twice daily (D+S) or S alone. For bilirubin ≥ 1.3x normal, D and S doses were halved. D was maxed out at 360 mg/m 2 . The study was stratified by extent of disease (locally advanced; metastatic), the primary endpoint was overall survival (OS); and secondary endpoint progression-free survival (PFS). The final analysis was to occur when 364 events were observed among 480 total patients, with 90% power to detect a 37% increase in median OS (10.7 to 14.7 months; 1-sided α = 0.05). Results: The Alliance DSMB halted the study after accrual of 346 patients (173 on each of D+S and S) when a futility boundary was crossed at a planned interim analysis. With 107 events in each arm, median OS was 9.3 months (95%CI 7.1-12.9) for D+S, and 10.5 months (95% CI 7.4-14.3) for S with a hazard ratio (HR) 1.06 (95% CI 0.8-1.4) for D+S vs. S. Median PFS was 3.6 (95% CI 2.8-4.6) and 3.2 months (95% CI 2.3-4.1), respectively (HR = 0.90, 95% CI 0.72-1.2). There were 38 deaths on treatment: 18 on D+S and 20 on S. Among these 8 [sepsis (1), dysphagia (1), pneumonia (1), cardiac (2), hepatic failure (2), and not otherwise specified (1)] on D+S, and 3 [fatigue (1), hepatic failure (1), and a secondary malignancy (1)] on S, were at least possibly related to treatment. A maximum grade 3 or 4 only hematologic adverse events (AE) occurred in 37.8% of patients on D+S and 8.1% of patients on S. Non-hematologic AEs were comparable, in 63.6% and 61.5% of patients, respectively. Conclusions: The addition of D to S resulted in higher toxicity and did not improve OS or PFS. The S median OS of about 10 months is consistent with previous reports. NCI Grant U10CA180821 Clinical trial information: NCT01015833.
Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite the primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in HCC, suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities. Here, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human proteins in hepatocellular carcinoma (HCC). A subset of the host factors targeted by HBV proteins were preferentially mutated in non-HBV-associated HCC, suggesting that their interaction with HBV influences HCC biology. HBV interacted with proteins involved in mRNA splicing, mitogenic signaling, and DNA repair, with the latter set interacting with the HBV oncoprotein X (HBx). HBx remodeled the PP2A phosphatase complex by excluding striatin regulatory subunits from the PP2A holoenzyme, and the HBx effects on PP2A caused Hippo kinase activation. In parallel, HBx activated mTOR complex 2 (mTORC2), which can prevent YAP degradation. mTORC2-mediated upregulation of YAP was observed in human HCC specimens and mouse HCC models and could be targeted with mTOR kinase inhibitors. Thus, HBV interaction with host proteins rewires HCC signaling rather than directly activating mitogenic pathways, provide an alternative paradigm for the cellular effects of a tumor promoting virus.
Somatic isocitrate dehydrogenase 1 mutations (IDH1m) convert α-ketoglutarate to the oncogenic metabolite R-2-hydroxyglutarate (2-HG). IDH1m are detected in approximately 13% of intrahepatic cholangiocarcinomas (CCAs).1 Ivosidenib, an oral inhibitor of the IDH1m protein inhibits 2-HG and restores immune response in CCA.2 We analyzed pre-treatment samples, using machine learning models to quantify histologic features of the CCA tumor microenvironment, enabling identification of correlates of IDH1m status, early disease progression (patients experienced progression or death within 1.54 months), and plasma 2-HG levels (median, 630 ng/ml).
Methods
A set of H&E images, including from ClarIDHy3, a phase 3 placebo controlled clinical trial of ivosidenib in IDH1m CCA, were split into training/validation (n=200) and test sets for model development. Whole slide images were annotated by GI pathologists to identify and quantify more than 500 different human interpretable features (HIFs), including cell (cancer cell, lymphocyte, macrophage, plasma cell, fibroblast) and tissue (cancer epithelium, stroma, necrosis) features. Utilizing IDH1m and wild type (WT) screening samples, multivariate logistic regression models were trained to predict IDH1m status. P-values were calculated by univariate logistic regression and corrected for multiple comparisons via adjustment for FDR.
Results
A HIF-based multivariate model discriminated between IDH1m and WT CCA (AUC, 0.83; 95% CI, 0.74-0.92). IDH1m was associated with a lower proportion of lymphocytes throughout the tumor (OR, 0.64; P<0.01; FDR P=0.022), and higher proportion of fibroblasts (OR, 1.8; P<0.01; FDR P=0.023) and lower proportion of plasma cells in the stroma (OR, 0.68; P<0.01; FDR P=0.032 ) (figure 1A). In a subset of samples, CD3 and CD8 staining showed reduced T-lymphocyte infiltration patterns in IDH1m (n=5) samples relative to IDH1 WT (n=19) (figure 1B). Early disease progression of enrolled ClarIDHy patients (ivosidenib n=61, placebo n=38) was associated with a higher proportion of macrophages (OR, 1.70; P<0.01; FDR P=0.08) and a lower proportion of tumor infiltrating lymphocytes (OR, 0.63; P<0.01; FDR P=0.08), (figure 2A). When correcting for treatment effect, the proportion of lymphocytes in the tumor were still associated with improved PFS (P=0.011). Consistent with previously published data2, high 2-HG levels were associated with lower numbers of tumor infiltrating lymphocytes (OR, 0.63; P=0.011; FDR P=0.08) (figure 2B).
Conclusions
Quantitative histologic evaluation suggests that pre-treatment IDH1m CCA samples have a colder tumor microenvironment relative to IDH1 WT CCA, with an immunosuppressive tumor microenvironment being associated with early progression. Results from this analysis support exploration of combination with immune checkpoint inhibitors.
Trial Registration
NCT02989857
References
Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J Gastrointest Oncol. 2019;10(4):751–765. doi: 10.21037/jgo.2019.03.10. Wu MJ, Shi L, Dubrot J, et al. Mutant IDH Inhibits IFN?-TET2 signaling to promote immunoevasion and tumor maintenance in cholangiocarcinoma. Cancer Discov. 2022;12(3):812–835. doi: 10.1158/2159-8290.CD-21-1077. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796–807. doi: 10.1016/S1470-2045(20)30157-1. Epub 2020 May 13. Erratum in: Lancet Oncol. 2020 Oct;21(10):e462.
Ethics Approval
This study was done according to the International Conference on Harmonisation of Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Approval from the institutional review board and international ethics committee was obtained at each study site. Patients provided written, informed consent before participating in the study.
