Explore the vast range of titles available.

Background: Biomarkers of therapeutic response and prognosis are needed to assist in the sequencing of treatments for metastatic castration-resistant prostate cancer (CRPC). Previously in a Phase 1 discovery study, we identified 14 circulating microRNAs that were associated with response to docetaxel chemotherapy or overall survival. We performed a Phase 2 validation study to verify these findings. Methods: Using real-time PCR, the levels of the 14 microRNAs were measured in plasma collected before and after the first cycle of docetaxel from a Phase 2 cohort of 89 patients. Results: The microRNAs were not associated with docetaxel response in the Phase 2 cohort. Higher baseline levels of six microRNAs, predominantly of the miR-200 family, were confirmed to be associated with shorter overall survival. A microRNA signature comprising these six microRNAs predicted high-risk patients in the Phase 2 cohort with a hazard ratio of 4.12 (95% CI 2.20–7.70, P =0.000001). The signature was an independent predictor in multivariable analysis with clinicopathological factors. Conclusions: The association of circulating microRNAs with overall survival suggests their involvement in CRPC progression.

In spite of demonstrating prognostic and possibly predictive benefit in retrospective cohorts and meta-analyses of cancer populations, including colorectal cancer (CRC), prospective evaluation of the relationship between neutrophil to lymphocyte ratio (NLR) and treatment outcomes in previously untreated mCRC patients receiving bevacizumab-based therapy has not yet been performed. An open-label, single arm, multi-centre study. Patients received first-line bevacizumab plus XELOX or mFOLFOX6 (Phase-A) and continued bevacizumab plus FOLFIRI beyond first progression (Phase-B). Analyses included the association of NLR with phase A progression free survival (PFS) and overall survival (OS). A sub-study investigated the safety in patients with the primary in situ tumor. An exploratory sub-study examined relationships of circulating proteomic markers with PFS. Phase-A enrolled 128 patients; median age was 64 years (range: 26-84), 70 (55%) were female, 71 (56%) were PS-0 and 51 (40%) had primary in situ tumor. Fifty-three (41%) patients entered Phase-B. The median baseline (b) NLR was 3.2 (range: 1.5-20.4) with 32 (25%) patients having bNLR > 5. The PFS hazard ratio (HR) by bNLR > 5 versus ≤ 5 was 1.4 (95% CI: 0.9-2.2; p = 0.101). The median PFS was 9.2 months (95% CI: 7.9-10.8) for Phase-A and 6.7 months (95% CI: 3.0-8.2) for Phase-B. The HR for OS based on bNLR > 5 versus ≤ 5 was 1.6 (95% CI: 1.0-2.7; p = 0.052). The median OS was 25 months (95% CI: 19.2-29.7) for the full analysis set and 14.9 months for Phase-B. Baseline levels of nine proteomic markers showed a relationship with PFS. Treatment related toxicities were consistent with what has previously been published. There were 4 (3%) instances of GI perforation, of which, 3 (6%) occurred in the primary in situ tumor group. Results from this study are aligned with the previously reported trend towards worse PFS and OS in patients with higher bNLR. ClinicalTrials.gov: NCT01588990; posted May 1, 2012.

Background Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC. Methods We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t -tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models. Results The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59–3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR , TP53, RB1 and PI3K aberrations ( p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts ( p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations ( p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN , was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies. Conclusions Elevated circulating sphingolipids were associated with AR , TP53 , RB1 , PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.

Aim There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non‐metastatic HER2‐positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long‐lasting toxicity. Hence, de‐escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real‐world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre. Methods This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non‐metastatic HER2‐positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post‐surgical prescribing patterns and also undertook survival analyses for invasive disease‐free survival (iDFS) as well as exploratory analyses for correlations between pre‐specified clinicopathologic factors and pathological response at surgery. Results Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease‐free at 3 years of follow‐up. Only 3 events of recurrence or death were recorded at a median follow‐up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery. Conclusion This study demonstrates that de‐escalated adjuvant treatment for HER2‐positive early breast cancer achieved favourable pathological and long‐term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components.

We present a case of cisplatin-induced syndrome of inappropriate antidiuretic hormone (SIADH) in a patient with metastatic recurrent urothelial carcinoma. Cisplatin-induced SIADH is an uncommon but potentially life-threatening toxicity. Pharmacogenetic characteristics may result in different toxicity profiles in different populations. With such widespread use of cisplatin in a diverse range of cancers, prompt recognition is crucial to detect and prevent severe neurological sequelae.

Purpose Vulvovaginal atrophy (VVA) is a commonly reported issue among breast cancer patients, and its aetiology is multifactorial. Treatment is difficult in these women, particularly because the use of oestrogens has traditionally been discouraged. Vaginal laser treatment has been reported to improve symptoms. We aimed to assess the impact on symptoms and sexual function of vaginal laser in women with early breast cancer (EBC). Methods We performed a single-arm investigator initiated pilot study of female EBC patients with symptomatic VVA. A total of 3 vaginal laser treatments were administered 4 weeks apart. Questionnaires were completed at baseline, 4, 8 and 12 weeks. Our primary endpoint was symptomatic improvement of VVA at 12 weeks on 10 cm visual analogue scales. Our secondary endpoints were improvement in sexual function using the Female Sexual Function Index (FSFI) and patient-reported improvements in symptoms, sexual function and quality of life. Statistical analysis was performed with a Wilcoxon Signed Rank test. Results 26 patients were enrolled between February 2016 and August 2017. All patients were post-menopausal, 25 of whom had received anti-oestrogen therapy for their breast cancer. Questionnaire compliance was high (98%) and all patients received the three pre-planned treatments. There was significant improvement in each of the VVA symptoms: dryness ( p  < 0.001), itch ( p  < 0.001), burning ( p  = 0.003), dysuria ( p  < 0.001) and dyspareunia ( p  < 0.001). Patients also reported improvement in sexual function on the FSFI ( p  ≤ 0.001). Conclusions Patients receiving vaginal laser had improvement in VVA symptoms and sexual function. Further randomised sham-controlled trials are needed to further assess this treatment.

In men with metastatic, hormone-sensitive prostate cancer who were receiving testosterone suppression, the addition of enzalutamide led to significantly longer progression-free and overall survival than the addition of standard nonsteroidal antiandrogen therapy. The better outcome was less clear among patients who had received docetaxel.

The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel. ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0–2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42. Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63–74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67–69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58–0·84]; p<0·0001), with 5-year overall survival of 57% (0·53–0·61) in the control group and 67% (0·63–0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3–4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1–3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment. The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients. Astellas Pharma.

Treatment options and prognosis remains poor for patients with recurrent glioblastoma multiforme. These tumors are highly vascularised and over express angiogenic factors such as vascular endothelial growth factor and may potentially be responsive to antiangiogenic therapies. We present the results of a phase II trial of Thalidomide, an antiangiogenic agent, in the treatment of recurrent glioblastoma multiforme. Patients were treated with 100 mg/day of Thalidomide, increased at weekly intervals by 100 mg to a maximum tolerated dose of 500 mg/d. Forty-two patients were enrolled, with 38 patients being assessable for response and 39 for toxicity. Two patients (5%) achieved a partial response and 16 (42%) had stable disease. The median survival was 31 weeks and the 1-year survival was 35%. Patients who had a partial response or stable disease had either a stabilisation or improvement in quality of life scores or performance status. Overall Thalidomide was well tolerated with no grade 4 toxicities and no treatment related deaths. The median maximum tolerated dose was 300 mg/day. The most common toxicity was fatigue to which patients developed tachyphylaxis. There was no correlation demonstrated with plasma vascular endothelial growth factor levels and response or survival. Thalidomide is a well-tolerated drug that may have some activity in the treatment of recurrent glioblastoma. Optimum dosing with antiangiogenic agents is currently under investigation. Chronic low dose therapy may be required to see conventional responses or improvements in time to progression. The dose required to achieve optimal biological impact may be better defined once we have established reliable surrogate endpoints.

Purpose Vulvovaginal atrophy (VVA) is a commonly reported issue among breast cancer patients, and its aetiology is multifactorial. Treatment is difficult in these women, particularly because the use of oestrogens has traditionally been discouraged. Vaginal laser treatment has been reported to improve symptoms. We aimed to assess the impact on symptoms and sexual function of vaginal laser in women with early breast cancer (EBC). Methods We performed a single-arm investigator initiated pilot study of female EBC patients with symptomatic VVA. A total of 3 vaginal laser treatments were administered 4 weeks apart. Questionnaires were completed at baseline, 4, 8 and 12 weeks. Our primary endpoint was symptomatic improvement of VVA at 12 weeks on 10 cm visual analogue scales. Our secondary endpoints were improvement in sexual function using the Female Sexual Function Index (FSFI) and patient-reported improvements in symptoms, sexual function and quality of life. Statistical analysis was performed with a Wilcoxon Signed Rank test. Results 26 patients were enrolled between February 2016 and August 2017. All patients were post-menopausal, 25 of whom had received anti-oestrogen therapy for their breast cancer. Questionnaire compliance was high (98%) and all patients received the three pre-planned treatments. There was significant improvement in each of the VVA symptoms: dryness (p < 0.001), itch (p < 0.001), burning (p = 0.003), dysuria (p < 0.001) and dyspareunia (p < 0.001). Patients also reported improvement in sexual function on the FSFI (p [less than or equal to] 0.001). Conclusions Patients receiving vaginal laser had improvement in VVA symptoms and sexual function. Further randomised sham-controlled trials are needed to further assess this treatment.