Assessing the effect of metastasis-directed therapy in oligometastatic disease using the restricted mean survival time.

BACKGROUND: Metastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) is emerging as an effective therapeutic option for oligometastatic disease (OMD). However, a lack of phase III data, consensus guidelines, and toxicity concerns limit its widespread use. Randomized controlled trials (RCTs) routinely report hazard ratios (HRs) and medians that lack clear clinical and robust interpretation. Restricted-mean survival time (RMST) is the duration of time a patient is expected to survive over the follow-up period, providing a robust and interpretable alternative. We analyzed the efficacy of SBRT using RMST. METHODS: All registered RCTs of ablative radiotherapy in OMD in ClinicalTrials.gov through 2022 were identified. Data were reconstructed from Kaplan-Meier curves, and the HRs and RMST differences were estimated for surrogate endpoints (SEs) and overall survival (OS). RESULTS: Six studies comprising 426 patients met the inclusion criteria. The RMST differences for SEs ranged from 4.6 months in a study by Iyengar et al. to 11.1 months in SABR-COMET. The RMST differences for OS in SABR-COMET, Gomez et al., and SINDAS studies were 12.6, 15 and 7.9 months, respectively. CONCLUSION: RMST demonstrates the efficacy of local treatment in OMD. Representing the expected survival time, this method effectively communicates outcomes to patients and clinicians.

Peptriever: a Bi-Encoder approach for large-scale protein-peptide binding search.

MOTIVATION: Peptide therapeutics hinge on the precise interaction between a tailored peptide and its designated receptor while mitigating interactions with alternate receptors is equally indispensable. Existing methods primarily estimate the binding score between protein and peptide pairs. However, for a specific peptide without a corresponding protein, it is challenging to identify the proteins it could bind due to the sheer number of potential candidates. RESULTS: We propose a transformers-based protein embedding scheme in this study that can quickly identify and rank millions of interacting proteins. Furthermore, the proposed approach outperforms existing sequence- and structure-based methods, with a mean AUC-ROC and AUC-PR of 0.73. AVAILABILITY AND IMPLEMENTATION: Training data, scripts, and fine-tuned parameters are available at https://github.com/RoniGurvich/Peptriever. The proposed method is linked with a web application available for customized prediction at https://peptriever.app/.

Differential Treatment Effects of Subgroup Analyses in Phase 3 Oncology Trials From 2004 to 2020.

Importance: Subgroup analyses are often performed in oncology to investigate differential treatment effects and may even constitute the basis for regulatory approvals. Current understanding of the features, results, and quality of subgroup analyses is limited. Objective: To evaluate forest plot interpretability and credibility of differential treatment effect claims among oncology trials. Design, Setting, and Participants: This cross-sectional study included randomized phase 3 clinical oncology trials published prior to 2021. Trials were screened from ClinicalTrials.gov. Main Outcomes and Measures: Missing visual elements in forest plots were defined as a missing point estimate or use of a linear x-axis scale for hazard and odds ratios. Multiplicity of testing control was recorded. Differential treatment effect claims were rated using the Instrument for Assessing the Credibility of Effect Modification Analyses. Linear and logistic regressions evaluated associations with outcomes. Results: Among 785 trials, 379 studies (48%) enrolling 331 653 patients reported a subgroup analysis. The forest plots of 43% of trials (156 of 363) were missing visual elements impeding interpretability. While 4148 subgroup effects were evaluated, only 1 trial (0.3%) controlled for multiple testing. On average, trials that did not meet the primary end point conducted 2 more subgroup effect tests compared with trials meeting the primary end point (95% CI, 0.59-3.43 tests; P = .006). A total of 101 differential treatment effects were claimed across 15% of trials (55 of 379). Interaction testing was missing in 53% of trials (29 of 55) claiming differential treatment effects. Trials not meeting the primary end point were associated with greater odds of no interaction testing (odds ratio, 4.47; 95% CI, 1.42-15.55, P = .01). The credibility of differential treatment effect claims was rated as low or very low in 93% of cases (94 of 101). Conclusions and Relevance: In this cross-sectional study of phase 3 oncology trials, nearly half of trials presented a subgroup analysis in their primary publication. However, forest plots of these subgroup analyses largely lacked essential features for interpretation, and most differential treatment effect claims were not supported. Oncology subgroup analyses should be interpreted with caution, and improvements to the quality of subgroup analyses are needed.

Association of differential censoring with survival and suboptimal control arms among oncology clinical trials.

Differential censoring (DC), referring to censoring imbalance between treatment arms, may bias the interpretation of survival outcomes in clinical trials. In 146 phase 3 oncology trials with statistically significant time-to-event surrogate primary endpoints (PEPs), we evaluated the association between DC in the surrogate PEP, control arm adequacy, and the subsequent statistical significance of OS results. Twenty-four (16%) trials exhibited DC favoring the control arm (ConDC), while 15 (10%) exhibited experimental arm DC (ExpDC). Positive OS was more common in ConDC trials (63%) than trials without DC (37%) or with ExpDC (47%; odds ratio [OR] 2.64, 95% CI 1.10-7.20; P=.04). ConDC trials more frequently used suboptimal control arms (46%) compared to 20% without DC and 13% with ExpDC (OR 3.60, 95% CI 1.29-10.0; P=.007). The presence of ConDC in trials with surrogate PEPs, especially in those with OS conversion, may indicate an inadequate control arm and should be examined and explained.

Projecting complete redaction of clinical trial protocols (RAPTURE): redacted cross sectional study.

OBJECTIVES: To characterise redactions in clinical trials and estimate a time when all protocols are fully removed (RAPTURE). DESIGN: Redacted cross sectional study. SETTING: Published phase 3 randomised controlled trials from 1 January 2010 to ██████████████. PARTICIPANTS: New England Journal of Medicine, ██████████, and Journal of the American Medical Association. MAIN OUTCOME MEASURES: █████ ████████ ██████████████ ██████ ██████████ ████████ ████████ ██████████ ███████████ ████████████ ████████████ ████████████████████████ ██████████████████ RESULTS: ████████████████████ met the inclusion criteria, with 268 (56.7%) research protocols available and accessible. The rate of redactions in protocols has increased from 0 in 2010 to 60.8% in 2021 (P<0.001). The degree of data redaction has also increased, with the average cumulative redactions among industry funded trials rising from 0 in 2010 to 3.5 pages in 2021 (P<0.001). Modelling predicts that RAPTURE is expected to occur between 2073 and 2136. Redactions featured predominantly in ████████ sponsored trials and mostly occurred in the statistical design. CONCLUSIONS: This study highlights the rise in protocol redactions and predicts that, ██████████████████████████████████████████ will be entirely redacted between 2073 and 2136. A legitimate rationale for the redactions could ███ be found. A multipronged strategy against protocol redactions is required to maintain the integrity of science. AVAILABILITY: This paper is partially redacted, but for the sake of ███████████, a version without any redactions can be found in the supplementary material.

FAK family proteins regulate in vivo breast cancer metastasis via distinct mechanisms.

Breast cancer is the most commonly diagnosed malignancy and the major leading cause of tumor-related deaths in women. It is estimated that the majority of breast tumor-related deaths are a consequence of metastasis, to which no cure exists at present. The FAK family proteins Proline-rich tyrosine kinase (PYK2) and focal adhesion kinase (FAK) are highly expressed in breast cancer, but the exact cellular and signaling mechanisms by which they regulate in vivo tumor cell invasiveness and consequent metastatic dissemination are mostly unknown. Using a PYK2 and FAK knockdown xenograft model we show here, for the first time, that ablation of either PYK2 or FAK decreases primary tumor size and significantly reduces Tumor MicroEnvironment of Metastasis (TMEM) doorway activation, leading to decreased intravasation and reduced spontaneous lung metastasis. Intravital imaging analysis further demonstrates that PYK2, but not FAK, regulates a motility phenotype switch between focal adhesion-mediated fast motility and invadopodia-dependent, ECM-degradation associated slow motility within the primary tumor. Furthermore, we validate our in vivo and intravital imaging results with integrated transcriptomic and proteomic data analysis from xenograft knockdown tumors and reveal new and distinct pathways by which these two homologous kinases regulate breast tumor cell invasiveness and consequent metastatic dissemination. Our findings identify PYK2 and FAK as novel mediators of mammary tumor progression and metastasis and as candidate therapeutic targets for breast cancer metastasis.

Prevalence and implications of significance testing for baseline covariate imbalance in randomised cancer clinical trials: The Table 1 Fallacy.

BACKGROUND: The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials. METHODS: From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy. RESULTS: A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating the typical 5% type I error assertion probability. Application of trial-level multiplicity corrections reduced the rate of significant findings to 0.3% (six of 2345 tests). Factors associated with lower odds of the Table 1 Fallacy included industry sponsorship (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.18-0.47; multiplicity-corrected P < 0.0001), larger trial size (≥795 versus <280 patients; aOR 0.32, 95% CI 0.19-0.53; multiplicity-corrected P = 0.0008), and publication in a European versus American journal (aOR 0.06, 95% CI 0.03-0.13; multiplicity-corrected P < 0.0001). CONCLUSIONS: This study highlights the persistence of the Table 1 Fallacy in contemporary oncology randomised controlled trials, with one of every four trials testing for baseline differences after randomisation. Significance testing is a suboptimal method for identifying unsound randomisation procedures and may encourage misleading inferences. Journal-level enforcement is a possible strategy to help mitigate this fallacy.

Gender Gap in Leadership of Clinical Trials.

This cross-sectional study investigates representation of women as principal investigators of clinical trials by study phase, medical specialty, and representation of women trial participants.

Attrition and withdrawal in multiple myeloma randomized controlled trials: A systematic review.

OBJECTIVES: Patients with multiple myeloma (MM) enrolled in randomized control trials (RCTs) discontinue treatment for various reasons; however, no prior study has analyzed reasons for discontinuation. We performed a systematic review of MM RCTs to investigate reasons for treatment discontinuation, imbalances between trial cohorts, and reporting practices. METHODS: A comprehensive search for RCTs in MM from 2015 to 2021 identified 45 studies meeting inclusion criteria. RESULTS: Of 21 236 randomized patients, 10 161 (47.8%) discontinued therapy by primary endpoint ascertainment. Causes of discontinuation included progression (n = 4790; 22.6% of randomized patients); toxicity (n = 2569; 12.1%); patient/physician withdrawal (n = 1200; 5.7%) and death (n = 495; 2.3%). Of randomized patients, 20 914 (98.5%) were included in the RCT analysis. Imbalances of attrition, defined as trials with greater than 5% absolute difference in discontinuation rate for reasons other than death, progression, and toxicity between intervention and control arms, were found in 11 (24.4%) studies. CONCLUSIONS: Although progression is the most common reason for RCT treatment discontinuation in patients with MM, over 10% discontinued due to toxicity. Furthermore, 24.4% of trials showed substantial imbalances between trial cohorts; raising concern for informative censoring and emphasizes the importance of detailed characterization of withdrawal in MM RCTs.

Assessment of Median and Mean Survival Time in Cancer Clinical Trials.

This cohort study assesses the relative stability of median and mean survival time estimates reported in cancer clinical trials.

Systemic structural analysis of alterations reveals a common structural basis of driver mutations in cancer.

A major effort in cancer research is to organize the complexities of the disease into fundamental traits. Despite conceptual progress in the last decades and the synthesis of hallmark features, no organizing principles governing cancer beyond cellular features exist. We analyzed experimentally determined structures harboring the most significant and prevalent driver missense mutations in human cancer, covering 73% (n = 168178) of the Catalog of Somatic Mutation in Cancer tumor samples (COSMIC). The results reveal that a single structural element-κ-helix (polyproline II helix)-lies at the core of driver point mutations, with significant enrichment in all major anatomical sites, suggesting that a small number of molecular traits are shared by most and perhaps all types of cancer. Thus, we uncovered the lowest possible level of organization at which carcinogenesis takes place at the protein level. This framework provides an initial scheme for a mechanistic understanding underlying the development of tumors and pinpoints key vulnerabilities.

A novel Pyk2-derived peptide inhibits invadopodia-mediated breast cancer metastasis.

Dissemination of cancer cells from the primary tumor into distant body tissues and organs is the leading cause of death in cancer patients. While most clinical strategies aim to reduce or impede the growth of the primary tumor, no treatment to eradicate metastatic cancer exists at present. Metastasis is mediated by feet-like cytoskeletal structures called invadopodia which allow cells to penetrate through the basement membrane and intravasate into blood vessels during their spread to distant tissues and organs. The non-receptor tyrosine kinase Pyk2 is highly expressed in breast cancer, where it mediates invadopodia formation and function via interaction with the actin-nucleation-promoting factor cortactin. Here, we designed a cell-permeable peptide inhibitor that contains the second proline-rich region (PRR2) sequence of Pyk2, which binds to the SH3 domain of cortactin and inhibits the interaction between Pyk2 and cortactin in invadopodia. The Pyk2-PRR2 peptide blocks spontaneous lung metastasis in immune-competent mice by inhibiting cortactin tyrosine phosphorylation and actin polymerization-mediated maturation and activation of invadopodia, leading to reduced MMP-dependent tumor cell invasiveness. The native structure of the Pyk2-PRR2:cortactin-SH3 complex was determined using nuclear magnetic resonance (NMR), revealing an extended class II interaction surface spanning the canonical binding groove and a second hydrophobic surface which significantly contributes to ligand affinity. Using structure-guided design, we created a mutant peptide lacking critical residues involved in binding that failed to inhibit invadopodia maturation and function and consequent metastatic dissemination in mice. Our findings shed light on the specific molecular interactions between Pyk2 and cortactin and may lead to the development of novel strategies for preventing dissemination of primary breast tumors predicted at the time of diagnosis to be highly metastatic, and of secondary tumors that have already spread to other parts of the body.

Systemic review of the robustness of randomized controlled trials for the treatment of cholangiocarcinoma in three domains: survival-inferred fragility index, restricted mean survival time, and the spin effect.

Background: The vast majority of patients with cholangiocarcinoma (CC) have advanced disease at diagnosis and are candidates for palliative treatment only. The robustness of the randomized controlled trials regarding the treatment of CC are assessed. Methods: A systematic review of all randomized control trials (RCT) of treatments for both intra- and extrahepatic CC between 2010 and 2020 was performed. The survival-inferred fragility index (SIFI; the minimum number of reassignments of the best survivors between arms that would overturn the statistical outcomes) was calculated. In addition, the gain, or loss, in survival in RCTs was evaluated by the restricted mean survival time (RMST) difference. Finally, the level of spin i.e., misrepresentation of study outcomes, was measured in inconclusive studies to assess distorted reporting strategies. Results: Out of 6,167 studies retrieved, 11 could be retained for full text revision (7 with both intra- and extrahepatic CC, 3 with peri-hilar CC, and 1 with peri-hilar or distal CC). Only 3 studies included resected patients (2 with both intra- and extrahepatic CC and 1 with peri-hilar or distal CC). Nine studies investigated systemic chemotherapy (including 3 after surgical resection), one study evaluated photodynamic therapy, and another investigated the use of an endoscopically inserted stent in the biliary tract. The median SIFI was -2 [interquartile range (IQR): -6.25, -0.25] across all studies. Overall, the median RMST difference was 0.56 months (IQR: 0.10, 0.95). Finally, for inconclusive studies, the level of spin was high, moderate, and low in respectively 12.5%, 25%, and 62.5% of the studies. Conclusions: RCTs of CC showed a low degree of robustness with a frequent proportion of associated spin.