Karen Chiam

Objective: To describe the patterns of care and factors associated with treatment uptake of localised prostate cancer, using the bi‐national Prostate Cancer Outcomes Registry–Australia and New Zealand (PCOR‐ANZ) database. Methods: Data for 36 504 patients, diagnosed between 2015 and 2018, from New Zealand and seven Australian jurisdictions were evaluated. Multinomial logistic regression was performed to identify factors associated with the likelihood of receiving no active treatment, radiotherapy (RT), androgen deprivation therapy (ADT) and combined ADT + RT, compared to radical prostatectomy (RP). Results: The most common disease risk group and treatment were intermediate‐risk disease (49.2%) and RP (40.3%). Men with low‐risk disease were mostly managed by no active treatment (81.5%). Compared to men treated with RP, the likelihood of receiving other treatments was higher in residents from regional areas, those from lower socio‐economic status (SES) areas and those diagnosed at regional or public hospitals. Being in the lowest SES group was associated with an odds ratio (OR) of 1.84, (95% confidence interval [CI] 1.67–2.02) of having no active treatment, an OR of 1.53 (95% CI 1.32–1.78) for RT, an OR of 2.66 (95% CI 2.10–3.36) for ADT and an OR of 2.56 (95% CI 2.23–2.93) for ADT + RT. Conclusions: Factors related to SES and hospital provider were associated with treatment choices in localised prostate cancer patients, independent of their age or disease risk classification.

A summary of local prostate cancer resources available to the general population and healthcare practitioners to support shared decision-making discussions.

Background: Prostate cancer (PC) aetiology is unclear. PC risk was examined in relation to several factors in a large population-based prospective study.Methods: Male participants were from Sax Institute’s 45 and Up Study (Australia) recruited between 2006 and 2009. Questionnaire and linked administrative health data from the Centre for Health Record Linkage and Services Australia were used to identify incident PC, healthcare utilisations, Prostate Specific Antigen (PSA) testing reimbursements and dispensing of metformin and benign prostatic hyperplasia (BPH) prescriptions. Multivariable Cox and Joint Cox regression analyses were used to examine associations by cancer spread, adjusting for various confounders.Results: Of 107,706 eligible men, 4257 developed incident PC up to end 2013. Risk of PC diagnosis increased with: PC family history (versus no family history of cancer; HR_adjusted = 1.36; 95% CI:1.21–1.52); father and brother(s) diagnosed with PC (versus cancer-free family history; HR_adjusted = 2.20; 95% CI:1.61–2.99); severe lower-urinary-tract symptoms (versus mild; HR_adjusted = 1.77; 95% CI:1.53–2.04) and vasectomy (versus none; HR_adjusted = 1.08; 95% CI:1.00–1.16). PC risk decreased with dispensed prescriptions (versus none) for BPH (HR_adjusted = 0.76; 95% CI:0.69–0.85) and metformin (HR_adjusted = 0.57; 95% CI:0.48–0.68). Advanced PC risk increased with vasectomy (HR_adjusted = 1.28; 95% CI:1.06–1.55) and being obese (versus normal weight; HR_adjusted = 1.31; 95% CI:1.01–1.69).Conclusion: Vasectomy and obesity are associated with an increased risk of advanced PC. The reduced risk of localised and advanced PC associated with BPH, and diabetes prescriptions warrants investigation.

Background: Population characteristics associated with the use of prostate biopsy are poorly understood. We described the use of diagnostic prostate biopsy and subsequent biopsy outcomes in a population-based Australian cohort. Methods: A total of 91,764 men from the Sax Institute's 45 and Up Study (New South Wales, Australia) recruited during 2006 to 2009 were included. Self-completed baseline questionnaires and linked administrative health data were used. Study period was from the date of recruitment to December 2013. Cox regression and logistic regression identified factors associated with receipt of biopsy and subsequent prostate cancer diagnosis. Results: During the study period, 5,089 participants had a diagnostic prostate biopsy, and 2,805 men (55.1% of those biopsied) received a cancer diagnosis. Men with a family history of prostate cancer (HR 1.55; 95% confidence interval (CI), 1.43–1.68), severe lower urinary tract symptoms (HR 1.62; 95% CI, 1.41–1.86), or a record of medication for benign prostatic hyperplasia (HR 1.34; 95% CI, 1.23–1.47) had increased risks of receiving a biopsy. Men with a family history of prostate cancer had increased odds of a positive biopsy (OR 1.21; 95% CI, 1.01–1.43). High alcohol consumption (≥21 drinks per week compared with 1–6 drinks per week) was associated with decreased risk of biopsy (HR 0.88; 95% CI, 0.80–0.96) but increased odds of a positive biopsy (OR 1.63; 95% CI, 1.32–2.02). Conclusions: Certain characteristics are associated with both undertaking diagnostic prostate biopsy and positive biopsy outcomes. Impact: This highlights the need to improve management of specific groups of men, especially those with clinical symptoms that overlap with prostate cancer, in their investigation for prostate cancer.

TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.

Background There is uncertainty on how multiparametric MRI (mpMRI) and MRI-targeted biopsy (MRI-TB) can be best used to manage low-risk prostate cancer patients on Active Surveillance (AS). We performed a scoping review to evaluate the benefits and harm associated with four different biopsy scenarios in which mpMRI can be implemented in AS. Methods Medline, Embase and Cochrane Library databases (1 January 2013–18 September 2020) were searched. Included studies were on men with low-risk prostate cancer enrolled in AS, who had mpMRI ± MRI-TB and standard prostate biopsy (systematic transrectal ultrasound or transperineal saturation biopsy), at confirmatory or follow-up biopsy. Primary outcomes were the number of Gleason score upgrades and biopsies avoided. Results Eight confirmatory biopsy studies and three follow-up biopsy studies were included. Compared to the benchmark of using standard biopsy (SB) for all men, the addition of MRI-TB increased the detection of Gleason score upgrades at both confirmatory (6/8 studies) and follow-up biopsy (3/3 studies), with increments of 1.7–11.8 upgrades per 100 men. 6/7 studies suggested that the use of a positive mpMRI to triage men for MRI-TB or SB alone would detect fewer Gleason score upgrades than benchmark at confirmatory biopsy, but the combination of MRI-TB and SB would detect more upgrades than the benchmark. For follow-up biopsy, the evidence on mpMRI triage biopsy scenarios was inconclusive due to the small number of included studies. Conclusions The addition of MRI-TB to benchmark (SB for all men) maximises the detection of Gleason score upgrades at confirmatory and follow-up biopsy. When the use of mpMRI to triage men for a biopsy is desired, the combination of MRI-TB and SB should be considered for men with positive mpMRI at confirmatory biopsy. The evidence on mpMRI triage scenarios was inconclusive in the follow-up biopsy setting.

Many patients with Oesophageal Adenocarcinoma (OAC) do not benefit from chemoradiotherapy treatment due to therapy resistance. To better understand the mechanisms involved in resistance and to find potential biomarkers, we investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, focusing on radiation. Intrinsic radiation resistance and chemotherapy drug resistance were assessed in eight OAC cell lines, and miRNA expression profiling was performed via TaqMan OpenArray qPCR. miRNAs discovered were either uniquely associated with resistance to radiation, cisplatin, or 5-FU, or were common to two or all three of the treatments. Target mRNA pathway analyses indicated several potential mechanisms of treatment resistance. miRNAs associated with the in vitro treatment responses were then investigated for association with pathologic response to neoadjuvant chemoradiotherapy (nCRT) in pre-treatment serums of patients with OAC. miR-451a was associated uniquely with resistance to radiation treatment in the cell lines, and with the response to nCRT in patient serums. Inhibition of miR-451a in the radiation resistant OAC cell line OE19 increased radiosensitivity (Survival Fraction 73% vs. 87%, p = 0.0003), and altered RNA expression. Pathway analysis of effected small non-coding RNAs and corresponding mRNA targets suggest potential mechanisms of radiation resistance in OAC.

A plethora of individual candidate biomarkers for predicting biochemical relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biomarkers associated with biochemical relapse. In the current study, these biomarkers were re‐analyzed for biochemical relapse, metastatic relapse and PCa death with extended follow‐up. Biomarkers of significance were then used to develop a combined prognostic model for clinical outcomes and validated in a large independent cohort. The discovery cohort (n = 324) was based on 12 biomarkers with a median follow‐up of 16 years. Seven biomarkers were significantly associated with biochemical relapse. Three biomarkers were associated with metastases: AZGP1, Ki67 and PML. Only AZGP1 was associated with PCa death. In their individual and combinational forms, AZGP1 and Ki67 as a dual BM signature was the most robust predictor of metastatic relapse (AUC 0.762). The AZPG1 and Ki67 signature was validated in an independent cohort of 347 PCa patients. The dual BM signature of AZGP1 and Ki67 predicted metastasis in the univariable (HR 7.2, 95% CI, 1.6–32; p = 0.01) and multivariable analysis (HR 5.4, 95% CI, 1.2–25; p = 0.03). The dual biomarker signature marginally improved risk prediction compared to AZGP1 alone (AUC 0.758 versus 0.738, p < 0.001). Our findings indicate that biochemical relapse is not an adequate surrogate for metastasis or PCa death. The dual biomarker signature of AZGP1 and Ki67 offers a small benefit in predicting metastasis over AZGP1 alone.

Background Clinical trials report improved overall survival following neoadjuvant chemoradiotherapy in patients undergoing surgery for esophageal adenocarcinoma, with a 10–15% survival improvement....