Comprehensive analysis of DNA damage repair deficiency in 10,284 pan-cancer study.

BACKGROUND: Disruption of the DNA damage repair (DDR) gene is related to cancer progression, treatment selection, and is subjected to radiation and targeted therapies with limited success. This paper conducted a comprehensive analysis to explore the distribution of DDR mutations in Chinese pan-cancer patients. METHODS: A total of 10,284 consecutive cases were analyzed in 24 cancer types [non-small cell lung cancer (NSCLC) 29.0%, liver 12.0%, colorectum 10.7%, etc.]. Tumor tissue samples were subjected to next generation sequencing (NGS) using a 381 gene panel incorporating 100 microsatellite loci. The association of deleterious somatic DDR mutation (del-sDDRmut) with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death-ligand 1 (PD-L1) expression of pan-cancers was evaluated. Genomic and clinical data from public cohorts of immunotherapy were analyzed to demonstrate the association between del-sDDRmut and clinical survival. RESULTS: Del-sDDRmut were found in 802 (7.6%) of all cases, and were most common in cancers of the endometrium, prostate, bladder, etc. cancer with a higher TMB also had a higher prevalence of mutations in DDR pathways. The results of the ridge regression analysis showed that 20 DDR genes were significantly associated with TMB [false discovery rate (FDR) <0.01]. A total of 8,899 patients had both TMB and MSI-data in pan-cancers. Seventy-four percent of patients with MSI-high (MSI-H) were accompanied by del-sDDRmut/TMB-high (TMB-H). The largest proportion of patients with microsatellite stability (MSS) with DDR mutations were classified as TMB-H. The top 6 tumors (NSCLC, melanoma, esophagus, head and neck, thyroid, and mediastinal) had the highest prevalence of PD-L1 ≥1%, and DDR mutations were significantly associated with a higher percent of PD-L1 positive (P<0.05). Furthermore, in the immune cohort analysis of NSCLC, patients with del-sDDRmut significantly improved median progression-free survival (mPFS) and median overall survival (mOS) compared to wild-type DDR patients (P=0.002 and P=0.043), with higher TMB observed (P<0.001). CONCLUSIONS: This study explored the association of DDR mutations with TMB, MSI-H, and PD-L1 expression, and revealed that patients with DDR mutations have a significantly improve prognosis than wild-type patients on immunotherapy.

Ablation Reboots the Response in Advanced Hepatocellular Carcinoma With Stable or Atypical Response During PD-1 Therapy: A Proof-of-Concept Study.

Background: The anti-programmed cell death protein-1 (PD-1) inhibitor is one of the second-line therapies for advanced hepatocellular carcinoma (HCC) after sorafenib failure. The goal of this study is to evaluate the feasibility and safety of ablation on the tumor in patients with advanced HCC who had stable disease or atypical response during single anti-PD-1 therapy after sorafenib failure. Atypical response defined as mixed responses in different lesions of the same individual (e.g., active or stable lesions mixed with progressive lesions). Patients and Methods: This proof-of-concept clinical trial enrolled 50 patients treated with an anti-PD-1 inhibitor of nivolumab or pembrolizumab monotherapy between July 2015 and Nov 2017. Thirty-three cases with stable disease or atypical response to anti-PD-1 inhibitor received subtotal thermal ablation. The safety and the response of ablation during anti-PD-1 therapy were evaluated. The survival was estimated by the Kaplan-Meier curve. Results: Of all 50 patients treated with anti-PD-1 therapy, the rate of response, stable disease, atypical and typical progression were 10% (n = 5), 42% (n = 21) 32% (n = 16), and 12% (n = 6), respectively. Additional ablation improved efficacy with tolerable toxicity, and the response rate was increased from 10 to 24% (12/50). The median time to progression, progression-free survival, and overall survival was 6.1 months (95%CI, 2.6-11.2), 5 months (95%CI, 2.9-7.1), and 16.9 months (95%CI, 7.7-26.1), respectively. Conclusions: This proof-of-concept trial suggested that additional ablation may increase the objective response rate with tolerated toxicity and achieved a relatively better median survival, in advanced HCC patients who had stable or atypical progressive diseases during anti-PD-1 therapy, which may provide a potentially promising strategy to treat advanced HCC. Trial registration number: ClinicalTrials.gov identifier: NCT03939975.

Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma.

BACKGROUND & AIMS: To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib. METHODS: This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16-82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models. RESULTS: The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months [RECIST]/7.4 vs. 3.6 months [mRECIST], respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio [HR] 0.389 [RECIST]/0.402 [mRECIST]; p <0.001 for each) and OS (HR 0.129; p <0.001). CONCLUSION: HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding. LAY SUMMARY: We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced hepatocellular carcinoma.

[Evaluating efficacy of transcatheter arterial chemo-embolization combined with radiofrequency ablation on patients with hepatocellular carcinoma by 18FDG-PET/CT].

BACKGROUND & OBJECTIVE: Judging tumor residue of hepatocellular carcinoma (HCC) after treatment of transcatheter arterial chemo-embolization (TACE) combined with radiofrequency ablation (RFA) by computed tomography (CT) scan is difficult; while 18-fluorodeoxyglucose-positron emission tomography/CT ((18)FDG-PET/CT) has some advantages in this aspect. This study was designed to compare the results of (18)FDG-PET/CT and CT scan in judging tumor residue of HCC after treatment of TACE combined with RFA, and to guide following treatment according to the result of (18)FDG-PET/CT. METHODS: Thirteen HCC patients with 18 lesions, 0.8-16.0 cm in diameter, were treated in Cancer Center of Sun Yat-sen University from Nov. 2002 to Jun. 2003. Of the 13 patients, 12 were naive patients with 15 lesions; 1 was relapsed with 3 lesions 1 year after hepatectomy. The results of CT and (18)FDG-PET/CT of the 13 patients 2-3 weeks after treatment of TACE combined with RFA were compared. If tumor residue was dictated, a further RFA treatment would be applied within 2-3 weeks. RESULTS: Of the 13 HCC patients that received 1 course of TACE combined with RFA, 11 had tumor residues which were conformed by fine needle biopsy and digital substraction angiography (DSA). CT only detected 5 positive cases; however, (18)FDG-PET/CT detected 10 positive cases. Positive rate of CT was 45.4%, and that of (18)FDG-PET/CT was 90.9%. According to the results of (18)FDG-PET/CT of the 11 patients, after the second course of RFA, 10 patients had no tumor residue; 1 patient survived with uncontrolled lesion 6 weeks after treatment. CONCLUSION: (18)FDG-PET/CT is better than CT in judging tumor residue of HCC after treatment of TACE combined with RFA or surgery, and in guiding further treatment of HCC.