JNCI Cancer Spectrum最新文献

Background: Bile acids are produced in the liver and are important for lipid digestion. Higher-circulating bile acid levels, however, have been linked to metabolic disorders, inflammation, and gut microbiota dysbiosis, which have been implicated in liver carcinogenesis. To date, few epidemiological studies have explored the association between circulating bile acids and liver cancer risk.

Methods: We conducted a nested case-control study among 12 prospective cohort studies located in the United States. Fifteen prediagnostic circulating bile acids were measured from blood samples among 872 individuals who developed liver cancer and 872 matched control participants. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted conditional logistic regression analysis of circulating bile acid levels and liver cancer risk.

Results: Primary conjugated bile acid concentrations were positively associated with higher risk of liver cancer (OR per doubling in concentrations [log2] and 95% CI of glycocholic acid: 1.32, 1.24 to 1.40; glycochenodeoxycholic acid: 1.33, 1.24 to 1.43; taurocholic acid: 1.28, 1.22 to 1.35; and taurchenodeoxycholic acid: 1.32, 1.24 to 1.39). Secondary conjugated bile acids were also positively associated with liver cancer risk (doubling of concentrations OR ranged from 1.11 to 1.22). Unconjugated bile acid concentrations were generally not associated with liver cancer risk, except lithocholic acid (OR per doubling: 1.27, 1.16 to 1.39). When analyses were separated into the 2 main subtypes of liver cancer, hepatocellular carcinoma (HCC; 438 cases/438 controls) and intrahepatic cholangiocarcinoma (ICC; 111 cases/111 controls), significant heterogeneity was observed for primary conjugated bile acid concentrations (all P < .001) that showed positive significant associations with HCC but not ICC.

Conclusions: These results suggest that bile acids may be important markers of HCC risk and contribute to hepatocarcinogenesis; however, further research using serial measurements is needed.

Background: Older adults with advanced prostate cancer and type 2 diabetes mellitus are underrepresented in trials of androgen receptor pathway inhibitors. This study examined changes in unplanned hospitalization rates in patients receiving androgen receptor pathway inhibitors by type 2 diabetes mellitus status and assessed if unplanned hospitalization varies according to androgen receptor pathway inhibitors.

Methods: This population-based study of advanced prostate cancer patients aged older than 66 years used Surveillance, Epidemiology, and End Results-Medicare data. Prepost androgen receptor pathway inhibitor initiation changes and androgen receptor pathway inhibitor differences in unplanned hospitalization rates were estimated by adjusted incidence rate ratio with considerations for interactions between period, androgen receptor pathway inhibitor, and type 2 diabetes mellitus status. Linear contrasts were used to estimate and test conditional incidence rate ratios. Tests were 2-sided, and a P value less than .05 was considered statistically significant.

Results: The study included 12 240 patients: 3160 (25.8%) with type 2 diabetes mellitus, 7191 (58.8%) received abiraterone acetate with prednisone, and 5049 (41.2%) received enzalutamide. Unplanned hospitalization rates increased after androgen receptor pathway inhibitor initiation by 65% among patients with type 2 diabetes mellitus complications (adjusted incidence rate ratio = 1.65, 95% confidence interval [CI] = 1.37 to 1.98) and 109% in nondiabetics (adjusted incidence rate ratio = 2.09, 95% CI = 1.94 to 2.26). Among patients with type 2 diabetes mellitus without complications, the increase in unplanned hospitalization rates depended on the androgen receptor pathway inhibitor initiated: 103% after abiraterone acetate with prednisone (adjusted incidence rate ratio = 2.03, 95% CI = 1.70 to 2.43) and 47% after enzalutamide (adjusted incidence rate ratio = 1.47, 95% CI = 1.21 to 1.80) and a 38% greater increase in unplanned hospitalization rates after abiraterone acetate with prednisone than enzalutamide (ratio of abiraterone acetate with prednisone adjusted incidence rate ratio divided by enzalutamide adjusted incidence rate ratio = 1.38, 95% CI = 1.06 to 1.80).

Conclusions: All patients had higher unplanned hospitalization rates after androgen receptor pathway inhibitor. Our findings highlight the importance of using real-world data to better understand the interplay between preexisting health conditions and treatment outcomes, a critical step toward precision medicine.

Background: The surrogacy of progression-free survival (PFS) for overall survival (OS) at the trial-level in randomized clinical trials (RCTs) testing immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancers (NSCLC) is influenced by several clinical-pathological factors. However, potential heterogeneity of PFS surrogacy according to patients' sex has never been investigated.

Methods: RCTs testing ICIs as monotherapy or combined with chemotherapy in patients with advanced NSCLC reporting hazard ratios (HRs) for PFS and OS according to patients' sex were included. The main objective was to assess sex-based heterogeneity in the trial-level association between PFS (surrogate endpoint) and OS (reference endpoint), overall and in subgroups defined by treatment type (ICIs as monotherapy vs ICIs plus chemotherapy). We used the coefficient of determination (R2) to quantify surrogacy.

Results: Twenty RCTs, for a total of 7528 male and 3008 female patients, were included. Overall, the association between OS-HR and PFS-HR was moderate: the R2 from a model adjusted by the type of treatment administered in the experimental arm was 0.69 (95% confidence interval [CI] = 0.34 to 0.88). Sex-disaggregated analysis showed heterogeneity in PFS surrogacy: the association was strong in male patients (adjusted R2 = 0.77; 95% CI = 0.56 to 0.89), but poor in female (adjusted R2 = 0.31, 95% CI = 0.03 to 0.63). Consistent results were obtained in subgroups analyses by treatment type, and in cross-validation analysis.

Conclusions: In RCTs testing ICIs alone or combined with chemotherapy in patients with advanced NSCLC, PFS is a robust surrogate endpoint for OS in male patients but not in female.

Background: Despite long-standing efforts to improve breast cancer care quality, wide performance gaps persist. We sought to identify regions demonstrating meaningfully low performance and characterize health-system and health-profession factors associated with geospatial disparities.

Methods: We used the Surveillance, Epidemiology, and End Results-Medicare linked database and the Health Resources and Services Administration area health resource file to characterize performance across health-care service areas using 4 metrics: diagnosis stage, chemotherapy, radiation, and endocrine therapy. We used principal component analysis to identify health-care facility and provider characteristics associated with performance; and hierarchical multivariable modeling to attribute total variance proportionally to 5 domains: patient characteristics, health service area region, health-care facility and provider characteristics, randomness, and unexplained.

Results: Among 31,571 women aged 66-79 diagnosed 2007-2013 with stage I-III breast cancer and treated with surgery, 61% had stage I disease, 23% received chemotherapy, 54% received radiation therapy, and 42% received endocrine therapy. Health system factors explained more variance for endocrine therapy (21%), chemotherapy (12%), and radiation therapy (12%), compared with geospatial region or patient characteristics. Health profession factors were associated with quality for stage, radiation therapy, and chemotherapy; health-care facility factors were associated with quality for stage, endocrine therapy, and chemotherapy. Patient characteristics explained <5% of observed variance.

Conclusions: Reassuringly, only a small number of regions demonstrated suboptimal breast cancer care. Optimal performance was associated with multidisciplinary teams and facilities with robust resources and higher volumes. Incorporating geospatial and health system factors into quality measurement efforts could foster the design of impactful quality improvement programs.

Background: The INTEGRATE phase 3 trial in advanced gastric and esophagogastric junction cancer involved pooling overall survival data with its preceding phase 2 trial, raising concerns about misalignment due to treatment switching in phase 2, or the "winner's curse." We evaluated phase 2 results, adjusted for these opposing effects, against phase 3 according to the prespecified statistical analysis plan.

Methods: Overall survival estimates were adjusted for treatment switching using the rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) method. A novel shrinkage approach mitigated overestimation from the winner's curse, and Bayesian prediction methods predicted phase 3 outcomes from phase 2 estimates. A simulation study modeled 10 000 seamless phase 2/3 trials to quantify bias in the pooled estimate.

Results: The observed phase 3 hazard ratio (HR = 0.71, 95% CI = 0.54 to 0.93) for overall survival was more conservative than the adjusted phase 2 estimates (RPSFTM and novel shrinkage approach: HR = 0.61, 95% CI = 0.29 to 1.29; RPSFTM and Bayesian prediction: HR = 0.59, 95% CI = 0.48 to 0.73; IPCW and novel shrinkage approach: HR = 0.55, 95% CI = 0.31 to 0.99; IPCW and Bayesian prediction: HR = 0.58, 95% CI = 0.46 to 0.72). Simulations indicated negligible bias in the pooled log hazard ratio of ‒0.011 and 0.005 under the null and alternative hypotheses, respectively.

Conclusion: Adjusting phase 2 estimates for both treatment switching and the winner's curse produced point estimates similar to the unadjusted phase 3 results. A prospective plan to pool trial data under a closed testing procedure may be a reasonable strategy when a recruitment shortfall in phase 3 is anticipated, provided that potential sources of misalignment are thoroughly assessed.

Clinical trial information: ACTRN12612000239864 (INTEGRATE I)NCT02773524 (INTEGRATE IIA).

Background: Residual or recurrent cancer after surgery but prior to adjuvant therapy occurs in a proportion of patients with head and neck cancer and may warrant treatment changes. 18-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) may help to identify residual or recurrent disease but is not routinely obtained. We evaluated the relevance of postoperative FDG-PET/CT in this clinical context.

Methods: This single-institution, retrospective study identified patients with head and neck cancer who underwent definitive surgery between January 1, 2013, and April 1, 2023, and received a postoperative FDG-PET/CT prior to adjuvant treatment. We measured the rates of management changes resulting from postoperative FDG-PET/CT findings and the association between having a postoperative FDG-PET/CT which resulted in a management change and oncologic outcomes with selected multivariable competing-risks and proportional hazards regressions.

Results: Of 150 patients, 66 (44.0%) had a management change because of the postoperative FDG-PET/CT findings; 62 (93.8%) had radiotherapy plan changes, 20 (30.3%) underwent additional diagnostic testing, 11 (16.7%) had systemic therapy added or changed, 3 (4.6%) underwent reresection, and 15 (10.0%) switched to palliative-intent treatment. Having a postoperative FDG-PET/CT that resulted in a management change was not significantly associated with cancer recurrence or overall survival (both P > .05).

Conclusions: In patients with resected head and neck cancer, postoperative, pre-adjuvant therapy FDG-PET/CT can alter clinical management and may enable additional personalization of treatment. When practical to obtain without delaying treatment, postoperative FDG-PET/CT may have clinical utility though requires careful interpretation due to the risks of false positives.

Background: Patients with cancer are at a higher risk of tuberculosis (TB) infection because of the immunosuppressive effect of prolonged chemotherapy. This study determined the prevalence of TB and TB-related deaths among patients with cancer from a global perspective.

Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to conduct the current study. Extracted data from relevant articles were analyzed using Stata, version 17.0, software (StataCorp LP). The effect size estimate was computed using a random-effects model, considering a 95% confidence interval (CI). The I2 statistic and Galbraith plot were used to confirm heterogeneity. A univariate meta-regression, sensitivity, and subgroup analyses were conducted to identify the source of heterogeneity. The Egger test and a funnel plot were used to check publication bias.

Results: In the 13 articles, of the 2 135 402 patients with malignancy, 31 073 had TB. The pooled estimate of TB was 3.69% (95% CI = 1.79% to 5.58%), with high heterogeneity (I2 = 99.99%). The pooled TB prevalence in Europe was 7.04 (95% CI = 1.09% to 12.99%). The prevalence of TB in a single study in North America was 8.78% (95% CI = 8.45% to 9.10%). A higher TB prevalence was observed in patients with solid tumors (6.84%, 95% CI = 4.30% to 9.38%), followed by hematologic malignancies and solid tumors (3.63%, 95% CI = 1.46% to 5.80%). Pulmonary and extrapulmonary TB were 3.05% and 0.77%, respectively. The rate of TB-related death was 0.04%. In meta-regression, publication year and sample size did not affect heterogeneity.

Conclusion: There is a considerable burden of TB (3.69%) in patients with cancer, which calls for routine TB screening and early treatment of cases to reduce complications.

Background: Retrospective analyses of studies of IO-containing combinations for advanced renal cell carcinoma (RCC) suggest that depth of response is associated with overall survival but have methodological limitations. We investigated the relationship of week 12 depth of response as a continuous variable with overall survival.

Methods: Pooling data from patients with treatment-naïve advanced RCC enrolled in randomized IO-containing frontline advanced RCC trials submitted to the US Food and Drug Administration that included week 12 imaging assessment, we developed 36-month overall survival prediction models based on week 12 depth of response (reduction from baseline in target lesion diameter) using Cox proportional hazards with natural spline in an IO combination group and a sunitinib group. To avoid guarantee-time bias, only patients in follow-up at the week 12 scan were included. Overall survival was defined from the week 12 imaging date.

Results: Among the 4 trials that met our inclusion criteria, 1364 patients in the IO combination group and 1267 patients in the sunitinib group had week 12 imaging. Depth of response and 36-month overall survival were correlated throughout the entire range of depth of response in both treatment groups, with no plateau in overall survival as depth of response approached complete response. Across this range, estimated 36-month overall survival was higher in the IO combination group.

Conclusions: Deeper response was associated with better 36-month overall survival in this pooled exploratory analysis of treatment-naïve patients with advanced RCC treated with IO combination or sunitinib. Further work characterizing the relationship between depth of response and overall survival at the trial level may advance understanding of the utility of depth of response as a pharmacodynamic response biomarker or early endpoint in signal-seeking trials and to facilitate efficient drug development.

Background: Personalized therapeutic approaches for localized prostate cancer have evolved significantly, with tissue-based biomarker tests supplementing traditional risk stratification tools. However, national testing patterns and geographic variability remain limited a decade after coverage implementation. We aimed to assess current nationwide utilization and urban-rural differences in tissue-based biomarker testing.

Methods: Using full Medicare claims data, we retrospectively identified patients with newly diagnosed prostate cancer and tissue-based biomarker testing claims from 2019 to 2023. Patients' county of residence was categorized as metro, urban, or rural. Regional testing rates were further assessed across hospital referral regions. A multivariable logistic regression model was performed to assess the effect of residence on test receipt.

Results: Our final cohort included 749 202 patients, of whom 79.5% lived in metro, 11.4% in urban and 8.00% in rural counties. Overall, 86 908 (11.6%) patients underwent tissue-based biomarker tests. Hospital referral region-level testing rates ranged from 2.4% to 42.7%. Rural patients were 18% less likely to undergo testing compared to metro patients (odds ratio [OR] 0.82, 95% CI = 0.73 to 0.91). Independently, the odds of undergoing testing were lower among Black (OR 0.82, 95% CI = 0.77 to 0.88) and Hispanic patients (OR 0.80, 95% CI = 0.73 to 0.88) compared to White patients.

Conclusion: This study reveals high geographic variability in tissue-based biomarker testing for prostate cancer. Further, Black and Hispanic patients were less likely to receive testing. Our findings highlight regional practice variation in the use of advanced, not routinely recommended tests and underscore the need to minimize disparities in diagnostic access.