BackgroundThere is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC.MethodsWe optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial).ResultsIn the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74–9.10; P < 0.001 and HR 3.81; 95% CI 2.28–6.37; P < 0.001, respectively], PFS (HR 2.18; 95% CI 1.08–4.39; P = 0.03, and HR 1.95; 95% CI 1.23–3.11; P = 0.01, respectively) and rate of PSA decline ≥50% [odds ratio (OR), 4.7; 95% CI 1.17–19.17; P = 0.035 and OR, 5.0; 95% CI 1.70–14.91; P = 0.003, respectively]. AR mutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47–not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94–9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26–19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16–56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts.ConclusionPlasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required.Clinical Trial numberNCT02288936 (PREMIERE trial).
Background Few studies have investigated the safety and efficacy of anti-PD-(L)1 antibodies in metastatic urothelial carcinoma (mUC) in daily clinical practice. Knowledge about the influence of baseline clinical and analytical factors on therapy outcomes is scarce. Patients and methods We conducted a multicenter retrospective study involving 119 previously treated or untreated mUC patients under anti-PD-(L)1 therapy in a real-world scenario. The objectives of this study were to confirm the safety and efficacy of anti-PD-(L)1 monotherapy and to identify pretreatment factors influencing therapy outcomes. In addition, an independent prognostic model for overall survival (OS) was developed and internally validated. Results Median OS was 7.8 months [95% confidence interval (CI), 5.4-10.4], median progression-free survival (PFS) was 2.80 months (95% CI, 2.4-3.4), disease control rate (DCR) was 40% (95% CI, 31-49), and overall response rate (ORR) was 24% (95% CI, 15-31). Presence of peritoneal metastases was associated with poor OS [hazard ratio (HR) = 2.40, 95% CI, 1.08-5.33; P = 0.03]. Use of proton-pump inhibitors (PPI) was associated with poor OS (HR = 1.83, 95% CI, 1.11-3.02; P = 0.02) and PFS (HR = 1.94, 95% CI, 1.22-3.09; P = 0.005), and lower DCR (OR = 0.38, 95% CI, 0.17-0.89; P = 0.03) and ORR (OR = 0.18, 95% CI, 0.02-1.60; P = 0.002). The three risk category prognostic model developed included Eastern Cooperative Oncology Group performance status, PPI use, albumin level, presence of liver metastases, and presence of peritoneal metastases variables and was associated with higher risk of death (HR = 3.00, 95% CI, 1.97-4.56; P = 0.0001). Conclusions This study confirms anti-PD-(L)1 monotherapy as a safe and effective treatment option in daily clinical practice for mUC patients. It also describes the presence of peritoneal metastases as an independent prognostic factor for OS and underlines the association between PPI use and worse therapeutic outcomes. Finally, it proposes a new easy-to-use risk-assessment model for OS prediction.
Over the past decade a number of vascular complications have emerged, such as newly developed or worsened hypertension, in patients who were administered with new cancer treatments for several types of cancer that were untreatable earlier. Hypertension is emerging as one of the most common adverse effects of therapy with angiogenesis inhibitors. Small-molecule inhibitors of vascular endothelial growth factor signalling are associated with a high proportion of patients with hypertension. The mechanisms underlying the development of hypertension are not well known, although there seem to be several mechanisms. Physiopathology of hypertension implicates abnormalities in endothelial function and angiogenesis. Several features of hypertensive patients are reduced number of arterioles and capillaries, alterations of the microvascular network, decrease in vascular wall compliance and flexibility, reduced nitric oxide bioactivity and increases in plasma vascular endothelial growth factor. Treatment with tyrosine kinase inhibitors (TKIs) is associated with a significant and sustained increase in blood pressure. We suspect that TKIs exert their hypertensive effects directly at the level of the microvascular network through processes such as vascular rarefaction, endothelial dysfunction and/or altered nitric oxide metabolism. This study shows the vascular complications of treatment with a TKI, sunitinib (SU11248), with special emphasis on hypertension.
We performed a literature search that shed light on the signaling pathways involved in the sorafenib activity as first- or subsequent-line treatment, taking into account its toxicity profile. Sorafenib appears to have better tolerability when compared with other agents in the same indication. Cross-resistance between tyrosine kinase inhibitors (TKIs) may be limited, even after failure with a previous VEGFR inhibitor, but the optimal sequence with TKIs remains to be determined. Randomized trials of second-line treatment options have showed either modest or no differences in terms of progression-free and overall survival (OS). Direct comparison between sorafenib and axitinib demonstrated differences in terms of PFS in favor of axitinib, but not in terms of OS as second-line treatment. In contrast, a phase III study showed a benefit in OS, favoring sorafenib when compared with temsirolimus. In conclusion, after using other VEGF inhibitor such as sunitinib, sorafenib is active and safe for the treatment of patients with advanced or metastatic RCC.
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