Association of Quality-of-Life Outcomes in Cancer Drug Trials With Survival Outcomes and Drug Class.

Importance: Although quality of life (QOL) is an important clinical end point, cancer drugs are often approved based on overall survival (OS) or putative surrogate end points such as progression-free survival (PFS) without QOL data. Objective: To ascertain whether cancer drug trials that show improvement in OS or PFS also improve global QOL of patients with cancer compared with the control treatment, as well as to assess how unchanged or detrimental QOL outcomes are reported in trial publications. Design, Setting, and Participants: This retrospective cohort study included all patients with cancer in the advanced setting who were enrolled into phase 3 randomized clinical trials (RCTs) of cancer drugs reporting QOL data and published in English language in a PubMed-indexed journal in the calendar year 2019. The systematic search of PubMed was conducted in July 2020. Main Outcomes and Measures: Association of QOL outcomes with OS and PFS, framing of unchanged QOL outcomes in trial publications, and the association of favorable framing with industry funding of the trials. Results: A total of 45 phase 3 RCTs enrolling 24 806 participants (13 368 in the experimental arm and 11 438 in the control arm) met the inclusion criteria and were included in the study analyses. Improvement in global QOL with the experimental agent was reported in 11 (24%) RCTs. The RCTs with improved QOL were more likely to also show improved OS vs trials with unimproved QOL (7 of 11 [64%] trials vs 10 of 34 [29%] trials; χ2 = 4.13; P = .04); there was no such association observed for PFS (6 of 11 [55%] trials vs 17 of 34 [50%] trials, χ2 = 0.03; P = .87). Six trials reported worsening QOL, of which 3 (50%) were trials of targeted drugs, and 11 trials reported improvement in QOL, of which 6 (55%) were trials of immunotherapy drugs. Of the 34 trials in which QOL was not improved compared with controls, 16 (47%) reported these results in a positive frame, an observation statistically significantly associated with industry funding (χ2 = 6.35; P = .01). Conclusions and Relevance: In this cohort study, a small proportion of RCTs of cancer drugs showed benefit in global QOL with the experimental agent. These results showed an association between QOL benefit and OS benefit but no such association with PFS benefit. Trials that failed to show improved QOL often reported their QOL outcomes more favorably. Non-immunotherapy-targeted drugs led to worse QOL more often than did cytotoxic agents.

Routine Surveillance of Chemotherapy Toxicities in Cancer Patients Using the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

INTRODUCTION: Systematic documentation of chemotoxicities in outpatient clinics is challenging. Incorporating patient-reported outcome (PRO) measures in clinical workflows can be an efficient strategy to strengthen the assessment of symptomatic treatment toxicities in oncology clinical practice. We compared the adequateness, feasibility, and acceptability of toxicity documentation using systematic, prospective, application of the PRO Common Toxicity Criteria for Adverse Events (PRO-CTCAE) tool. METHODS: At a comprehensive cancer center, data abstraction of electronic health record reviews elucidated current methods and degree of chemotoxicity documentation. Web-based 32-item PRO-CTCAE questionnaires, administered in ambulatory clinics of patients receiving chemotherapy, captured chemotoxicities and respective severities. Patient telephone surveys assessed whether healthcare providers had addressed chemotoxicities to the patients' satisfaction. RESULTS: Over a broad demographic of 497 patients receiving chemotherapy, 90% (95% CI 84-96%) with significant chemotoxicities (n = 107) reported that their providers had discussed toxicities with them; of these, 70% received a therapy management change, while among the rest, 17% desired a change in management. Of patients surveyed, 91% (95% CI 82-99%) were satisfied with their current chemotoxicity management. Clinician chart documentation varied greatly; descriptors rather than numerical grading scales were typically used. Although 93% of patients were willing to complete the PRO survey, only 50% thought that it would be acceptable to complete this survey at routine clinic visits. CONCLUSION: Use of PRO-CTCAE in routine clinical practice promotes systematic evaluation of symptomatic toxicities and improves the clarity, consistency, and efficiency of clinician documentation; however, methods to improve patient willingness to complete this tool routinely are needed.

miRNAs dysregulated in association with Gleason grade regulate extracellular matrix, cytoskeleton and androgen receptor pathways.

The Gleason grading system is an important determinant of treatment decisions and prognosis in prostate cancer. It has a number of limitations, including significant inter-observer variability, creating a need for biological parameters to accurately assess the Gleason grade. The objective of this study was to determine the molecular correlates of the different Gleason grades. Global miRNA expression was analysed in pure regions of each Gleason grade. Bioinformatics analysis was performed to predict miRNA-mediated signalling. We experimentally validated the effect of miRNAs on target gene expression and cellular functions using cell line models. We also examined the correlation of miRNAs with biochemical failure, metastasis and prognosis. We identified miRNAs that are differentially expressed between grades 3 and 5, and the top biological processes associated with Gleason grade transition were extracellular matrix (ECM)-mediated signalling, focal adhesion kinase- and mitogen-activated kinase pathways. Transfection with miR-29c, miR-34a and miR-141 repressed genes involved in ECM-mediated pathways, such as SRC, PRKCA, COL1A1, ITGB1 and MAPK13, and decreased cell proliferation and migration. Furthermore, miR-29c and miR-34a influenced downstream pathways that affect actin cytoskeleton organization and androgen receptor localization. Finally, miR-29c, miR-34a, miR-141 and miR-148a showed inverse correlations with biochemical recurrence, but were independent of other clinical parameters. Our results demonstrate the potential role of miRNAs as independent prognostic markers and pave the road for a biological-based reclassification of the Gleason grading system.

Kallikrein-related peptidase 5 induces miRNA-mediated anti-oncogenic pathways in breast cancer.

Kallikrein-related peptidase 5 (KLK5) displays aberrant expression in cancer. Recently, we showed KLK5 reconstitution in breast cancer cell lines suppresses malignancy. Present study aims to investigate the functional KLK5 mediated miRNA network on breast cancer progression, molecular subtype and survival. 28 miRNAs were up-regulated and 62 miRNAs were down-regulated upon KLK5 expression. Extracellular matrix (ECM) molecules and cell-adhesion pathways were the most significant KLK5-induced miRNA-mediated regulatory targets. Validation from The Cancer Genome Atlas (TCGA) database indicated KLK5 was specifically down-regulated in luminal B and basal-like breast cancer subtypes. There was a correlation between KLK5, miRNAs and their downstream ECM gene targets. Long-term patient survival correlated with dysregulation of KLK5 and interacting ECM target genes. It suggests biological differences between breast cancer molecular subtypes, patient survival, and their propensity for invasion and metastasis can be explained in part by altered miRNA networks induced by KLK5 dysregulation. We provide the first evidence that KLK5 can affect miRNA networks, which regulate MMPs and other novel ECM targets and a new compelling hypothesis of interplay between serine proteases and miRNAs. We developed a combined KLK5-(ITGB1+COL12A1) predictive score for recurrence-free survival that could be exploited in clinical applications.