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Mahon K.L.,1 Chris OBrien Lifehouse | Mahon K.L.,Garvan Institute of Medical Research | Mahon K.L.,University of New South Wales | Qu W.,Garvan Institute of Medical Research | And 18 more authors.
British Journal of Cancer | Year: 2014

Background:Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). Methods:Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. Results:The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). Conclusions:We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.British Journal of Cancer advance online publication, 21 August 2014; doi:10.1038/bjc.2014.463 www.bjcancer.com.


Freeman J.A.,University of Sydney | Freeman J.A.,Northern Haematology and Oncology Group | Freeman J.A.,Chronic Lymphocytic Leukaemia Australian Research Consortium CLLARC | Crassini K.R.,University of Sydney | And 12 more authors.
Leukemia and Lymphoma | Year: 2013

Hypogammaglobulinemia is a common complication of chronic lymphocytic leukemia (CLL), but the significance of immunoglobulin G (IgG) subclass deficiency is unknown. We analyzed the prevalence of immunoglobulins G, A and M, IgG subclass deficiency and infection in 150 patients with CLL. Low IgG, IgA and IgM levels were observed in 27.3%, 30.7% and 56.7% of patients, respectively. IgG subclass deficiency was frequent, with reduced IgG1, IgG2, IgG3 and IgG4 in 28%, 19.3%, 52% and 22.7% of patients, respectively. IgG subclass deficiency (total 64.6%) and hypogammaglobulinemia (27.3%) were more prevalent than clinically significant infection (16%). Recurrent or significant infections were seen in 24 patients (16%), of whom 50% had hypogammaglobulinemia but 100% had at least one IgG subclass deficiency, indicating that half the patients with infection had IgG subclass deficiency but normal total IgG level. Deficiencies of IgG3 and IgG4 were statistically associated with infection risk. Normal immunoglobulin and IgG subclass levels were seen in 26 patients (17%) and none had infections. IgG subclass deficiency is commonly observed in patients with CLL with both normal and reduced total IgG levels, and is associated with infection. Screening patients with CLL for IgG subclass deficiency may be a useful adjunct in stratifying their infection risk. © 2013 Informa UK, Ltd.


Lin H.-M.,Garvan Institute of Medical Research | Castillo L.,Garvan Institute of Medical Research | Mahon K.L.,Garvan Institute of Medical Research | Mahon K.L.,University of Sydney | And 20 more authors.
British Journal of Cancer | Year: 2014

Background:Docetaxel is the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, response rates are ∼50% and determined quite late in the treatment schedule, thus non-responders are subjected to unnecessary toxicity. The potential of circulating microRNAs as early biomarkers of docetaxel response in CRPC patients was investigated in this study.Methods:Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients.Results:Fourteen microRNAs were associated with serum prostate-specific antigen (PSA) response or overall survival, according to Mann-Whitney U or log-rank tests. Non-responders to docetaxel and patients with shorter survival generally had high pre-docetaxel levels of miR-200 family members or decreased/unchanged post-docetaxel levels of miR-17 family members. Multivariate Cox regression with bootstrapping validation showed that pre-docetaxel miR-200b levels, post-docetaxel change in miR-20a levels, pre-docetaxel haemoglobin levels and visceral metastasis were independent predictors of overall survival when modelled together.Conclusions:Our study suggests that circulating microRNAs are potential early predictors of docetaxel chemotherapy outcome, and warrant further investigation in clinical trials. © 2014 Cancer Research UK.


Mahon K.L.,Chris oBrien Lifehouse | Mahon K.L.,Garvan Institute of Medical Research | Mahon K.L.,University of Sydney | Lin H.-M.,Garvan Institute of Medical Research | And 18 more authors.
British Journal of Cancer | Year: 2015

Background:Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort.Methods:PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response.Results:PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1β, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002).Conclusions:In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC. © 2015 Cancer Research UK. All rights reserved.


Mahon K.L.,Chris oBrien Lifehouse | Mahon K.L.,Garvan Institute of Medical Research | Mahon K.L.,University of Sydney | Qu W.,Garvan Institute of Medical Research | And 18 more authors.
British Journal of Cancer | Year: 2014

Background:Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS).Methods:Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay.Results:The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007).Conclusions:We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted. © 2014 Cancer Research UK.

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