Project description:Background. Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor protein which lacks the ligand-binding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of AR-V7 in circulating tumor cells (CTCs) from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods. We used quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with metastatic castration-resistant prostate cancer initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status and PSA response rates, PSA-progression-free-survival (PSA-PFS), clinical/radiographic-progression-free-survival (PFS), and overall survival (OS). Multivariable Cox regression analyses were performed to determine the independent effect of AR-V7 status on clinical outcomes. Results. Thirty-one enzalutamide-treated patients and thirty-one abiraterone-treated patients were enrolled, of which 38.7% and 19.4% had detectable AR-V7 from CTCs, respectively. Among men receiving enzalutamide, AR-V7–positive patients had inferior PSA response rates (0% vs 52.6%, P=0.004), PSA-PFS (median: 1.4 vs 6.0 months, P<0.001), PFS (median: 2.1 vs 6.1 months, P<0.001), and OS (median: 5.5 months vs not reached, P=0.002) compared to AR-V7–negative patients. Similarly, among men receiving abiraterone, AR-V7–positive patients had inferior PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median: 1.3 months vs not reached, P<0.001), PFS (median: 2.3 months vs not reached, P<0.001), and OS (median: 10.6 months vs not reached, P=0.006). The negative prognostic impact of AR-V7 was maintained after adjusting for full-length-AR expression. Conclusions. Detection of AR-V7 in CTCs from patients with castration-resistant prostate cancer is associated with resistance to enzalutamide and abiraterone.

Project description:Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA. Locally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration. Between May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intra-tumoral CD8+ T cell density) in baseline tumour tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination. FOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy.

Project description:Background. Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor protein which lacks the ligand-binding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of AR-V7 in circulating tumor cells (CTCs) from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods. We used quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with metastatic castration-resistant prostate cancer initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status and PSA response rates, PSA-progression-free-survival (PSA-PFS), clinical/radiographic-progression-free-survival (PFS), and overall survival (OS). Multivariable Cox regression analyses were performed to determine the independent effect of AR-V7 status on clinical outcomes. Results. Thirty-one enzalutamide-treated patients and thirty-one abiraterone-treated patients were enrolled, of which 38.7% and 19.4% had detectable AR-V7 from CTCs, respectively. Among men receiving enzalutamide, AR-V7–positive patients had inferior PSA response rates (0% vs 52.6%, P=0.004), PSA-PFS (median: 1.4 vs 6.0 months, P<0.001), PFS (median: 2.1 vs 6.1 months, P<0.001), and OS (median: 5.5 months vs not reached, P=0.002) compared to AR-V7–negative patients. Similarly, among men receiving abiraterone, AR-V7–positive patients had inferior PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median: 1.3 months vs not reached, P<0.001), PFS (median: 2.3 months vs not reached, P<0.001), and OS (median: 10.6 months vs not reached, P=0.006). The negative prognostic impact of AR-V7 was maintained after adjusting for full-length-AR expression. Conclusions. Detection of AR-V7 in CTCs from patients with castration-resistant prostate cancer is associated with resistance to enzalutamide and abiraterone. A total of four metastatic castration-resistant prostate tumor samples from four patients were subjected to RNA-seq. Two samples were positive for androgen receptor splice variant 7 and the other two were negative for this variant.

Project description:Background: Recent data demonstrated efficacy of immune checkpoint inhibitors in advanced OCCC, but little is known about the immune microenvironment of these tumours and its impact on outcomes. We studied the expression of a panel of immune response genes in OCCC to identify the presence and prognostic relevance of irGES in these tumours. Methods: Immune response gene profiling was performed on 96 FFPE OCCC tumour samples with matched clinical outcomes, collected from the National University Hospital, Singapore between 2003 – 2016, using the nanoString nCounter PanCancer Immune Profiling Panel. Unsupervised hierarchical clustering analysis was performed to stratify OCCCs to derive the irGES profiles. Upregulation of specific genes of interest at the protein level and the status of mismatch repair (MMR) and ARID1A were validated using immunohistochemistry (IHC). Results: Total of 74/84 samples were successfully profiled. Median age at diagnosis was 53 yrs. 41 (55.4%) were stage 1, 7 (9.5%) stage 2, 24 (32.4%) Stage3, 2 (2.7%) stage 4. 64/74 (86.5%) of patients received adjuvant chemotherapy post debulking surgery with 38% recurrence rate (median PFS 27 months). Median follow up was 36 months. Based on irGES, 4 distinct molecular subgroups of OCCCs were identified. G1 was hallmarked by NK cell markers and PD-1 expression (PD-1 high), G2 by increased CTLA-4 expression, G3 by upregulation of genes associated with immunogenicity and antigen presentation, and G4 by increased levels of pro - angiogenic genes. The PD-1 high group was observed to have significantly poorer PFS (median PFS 20 months vs 68 months, p= 0.011) and a trend towards poorer OS when compared with G2/3/4 (median OS 38.8 months vs undefined, p = 0.0501). The pro - angiogenic (G4) carried the best prognosis (median PFS 108 months vs 26 months, p= 0.0515; median OS undefined, p= 0.0726). This difference in OS and PFS was consistently observed between stage 1 and non-stage 1 pts (hazard ratio 5.856 and 5.659, p < 0.0001, respectively). Significant correlation was observed between gene and protein expression of tumour PD-1, tumour and stromal PD-L1, and tumour IL-6 using IHC (p < 0.0001 for all comparisons). 6 (8.1%) pts were MMR deficient and there was no significant association between ARID1A and MMR expression across each irGES groups. Conclusion: OCCCs are heterogeneous and can be classified into 4 molecular subgroups based on their irGES profiles representing distinct clinicopathological characteristics and prognostic outcomes. If validated in larger datasets, these signatures may serve to guide clinical trial design and personalized treatment for OCCC pts.

Project description:We report the RNA sequencing data from the REPEAT study, in which patients with beyond first-line esophagogastric cancer were treated with regorafenib and paclitaxel. For the RNA sequencing, biopsies from metastatic lesions were obtained on baseline (n=21) and fifteen days following treatment initiation (n=13). PURPOSE: Regorafenib monotherapy, a multikinase-inhibitor of angiogenesis, tumor microenvironment, and oncogenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in advanced esophagogastric cancer (EGC) patients refractory to first-line treatment, and explore potential biomarkers. METHODS: Patients received paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on day 1-21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall- (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second/third line systemic treatment. Paclitaxel pharmacokinetics were assessed using D1 and D15 samples. We performed ELISA measurements of galectin-1, RNA sequencing and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses. RESULTS: In the dose-escalation cohort (n=14), the MTD of regorafenib was 120 mg. Thirty-four patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade ≥3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up 7.8 months). OS (p=0.08) and PFS (p=0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p<0.05); no associations were observed with toxicity or efficacy. An increase in circulating galectin-1 compared to baseline was associated with shorter OS (p<0.01). Enrichment of angiogenesis-related gene expression was observed in short-survivors measured by RNA sequencing. Chromosome 19q13.12-q13.2 amplification was associated with shorter OS (p=0.02) and PFS (p=0.02). CONCLUSION: Treatment with regorafenib and paclitaxel is tolerable and shows promising efficacy in advanced EGC refractory to first-line treatment. Galectin-1 and chromosome 19q13.12-q13.2 amplification could serve as negative predictive biomarkers for treatment response.

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TACE Plus HAIC Combined With Regorafenib for Liver Metastasis of Colorectal Cancer Refractory to Standard Treatment Regimens

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